Boronic acid derivatives and therapeutic uses thereof

ABSTRACT

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

The present application is divison of U.S. application Ser. No.16/378,323, filed Apr. 8, 2019 and to be issued as U.S. Pat. No.10,570,159, which is a continuation of U.S. application Ser. No.15/636,424, filed Jun. 28, 2017, now U.S. Pat. No. 10,294,249, whichclaims the benefit of priority to U.S. Provisional Appl. No. 62/357,165,filed Jun. 30, 2016, each of which is incorporated by references in itsentirety.

BACKGROUND Field

The present application relates to the fields of chemistry and medicine.More particularly, the present application relates to boronic acidantimicrobial compounds, compositions, their preparation, and their useas therapeutic agents.

Description of the Related Art

Antibiotics have been effective tools in the treatment of infectiousdiseases during the last half-century. From the development ofantibiotic therapy to the late 1980s there was almost complete controlover bacterial infections in developed countries. However, in responseto the pressure of antibiotic usage, multiple resistance mechanisms havebecome widespread and are threatening the clinical utility ofanti-bacterial therapy. The increase in antibiotic resistant strains hasbeen particularly common in major hospitals and care centers. Theconsequences of the increase in resistant strains include highermorbidity and mortality, longer patient hospitalization, and an increasein treatment costs.

Various bacteria have evolved β-lactam deactivating enzymes, namely,β-lactamases, that counter the efficacy of the various β-lactamantibiotics. β-lactamases can be grouped into 4 classes based on theiramino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes inclasses A, C, and D include active-site serine β-lactamases, and class Benzymes, which are encountered less frequently, are Zn-dependent. Theseenzymes catalyze the chemical degradation of β-lactam antibiotics,rendering them inactive. Some β-lactamases can be transferred within andbetween various bacterial strains and species. The rapid spread ofbacterial resistance and the evolution of multi-resistant strainsseverely limits β-lactam treatment options available.

The increase of class D β-lactamase-expressing bacterium strains such asAcinetobacter baumannii has become an emerging multidrug-resistantthreat. A. baumannii strains express A, C, and D class β-lactamases. Theclass D β-lactamases such as the OXA families are particularly effectiveat destroying carbapenem type β-lactam antibiotics, e.g., imipenem, theactive carbapenems component of Merck's Primaxin® (Montefour, K. et al.,Crit. Care Nurse 2008, 28, 15; Perez, F. et al., Expert Rev. AntiInfect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J., Antimicrob.Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al., J.Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed apressing threat to the effective use of drugs in that category to treatand prevent bacterial infections. Indeed the number of cataloguedserine-based β-lactamases has exploded from less than ten in the 1970sto over 300 variants. These issues fostered the development of five“generations” of cephalosporins. When initially released into clinicalpractice, extended-spectrum cephalosporins resisted hydrolysis by theprevalent class A β-lactamases, TEM-1 and SHV-1. However, thedevelopment of resistant strains by the evolution of single amino acidsubstitutions in TEM-1 and SHV-1 resulted in the emergence of theextended-spectrum β-lactamase (ESBL) phenotype.

New β-lactamases have recently evolved that hydrolyze the carbapenemclass of antimicrobials, including imipenem, biapenem, doripenem,meropenem, and ertapenem, as well as other β-lactam antibiotics. Thesecarbapenemases belong to molecular classes A, B, and D. Class Acarbapenemases of the KPC-type predominantly in Klebsiella pneumoniaebut now also reported in other Enterobacteriaceae, Pseudomonasaeruginosa and Acinetobacter baumannii. The KPC carbapenemase was firstdescribed in 1996 in North Carolina, but since then has disseminatedwidely in the US. It has been particularly problematic in the New YorkCity area, where several reports of spread within major hospitals andpatient morbidity have been reported. These enzymes have also beenrecently reported in France, Greece, Sweden, United Kingdom, and anoutbreak in Germany has recently been reported. Treatment of resistantstrains with carbapenems can be associated with poor outcomes.

The zinc-dependent class B metallo-β-lactamases are represented mainlyby the VIM, IMP, and NDM types. IMP and VIM-producing K. pneumonia werefirst observed in 1990s in Japan and 2001 in Southern Europe,respectively. IMP-positive strains remain frequent in Japan and havealso caused hospital outbreaks in China and Australia. However,dissemination of IMP-producing Enterobacteriaceae in the rest of theword appears to be somewhat limited. VIM-producing enterobacteria can befrequently isolated in Mediterranean countries, reaching epidemicproportions in Greece. Isolation of VIM-producing strains remains low inNorthern Europe and in the United States. In stark contrast, acharacteristic of NDM-producing K. pneumonia isolates has been theirrapid dissemination from their epicenter, the Indian subcontinent, toWestern Europe, North America, Australia and Far East. Moreover, NDMgenes have spread rapidly to various species other than K. pneumonia.

The plasmid-expressed class D carbapenemases belong to OXA-48 type.OXA-48 producing K. pneumonia was first detected in Turkey, in 2001. TheMiddle East and North Africa remain the main centers of infection.However, recent isolation of OXA-48-type producing organisms in India,Senegal and Argentina suggest the possibility of a global expansion.Isolation of OXA-48 in bacteria other than K. pneumonia underlines thespreading potential of OXA-48.

Treatment of strains producing any of these carbapenemases withcarbapenems can be associated with poor outcomes.

Another mechanism of β-lactamase mediated resistance to carbapenemsinvolves combination of permeability or efflux mechanisms combined withhyper production of beta-lactamases. One example is the loss of a porincombined in hyperproduction of ampC beta-lactamase results in resistanceto imipenem in Pseudomonas aeruginosa. Efflux pump over expressioncombined with hyperproduction of the ampC β-lactamase can also result inresistance to a carbapenem such as meropenem.

Thus, there is a need for improved β-lactamase inhibitors (BLIs).

SUMMARY

Some embodiments described herein relate to compounds having thestructure of the Formula I or II, or pharmaceutically acceptable saltsthereof:

wherein

Y¹ is N or CR⁴;

m is an integer of 0 or 1;

(a)

R² and R³ together with the atoms to which they are attached form afused ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, each optionally substituted with one or more R⁵,and

each of R¹, R⁴, R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(c))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or (b)

R³ and R⁴ together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R¹, R², R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or (c)

R¹ and R² together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R³, R⁴, R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or (d)

R^(a) and R^(b) together with the atoms to which they are attached forma spirocyclic ring or ring system selected from the group consisting ofC₃₋₇ carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R¹, R², R³, and R⁴ is independently selected from the groupconsisting of H, amino, halogen, cyano, hydroxy, optionally substitutedC₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy,optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S(O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or (e)

R^(a) and R⁴ together with the atoms to which they are attached form afused ring or ring system selected from the group consisting of C₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, each optionally substituted with one or more R⁵, and

each of R¹, R², R³, and R^(b) is independently selected from the groupconsisting of H, amino, halogen, cyano, hydroxy, optionally substitutedC₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy,optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d);

R⁵ is —Y⁵—(CH₂)_(t)-G;

t is an integer of 0 or 1;

G is selected from the group consisting of H, amino, halogen, cyano,hydroxy, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆haloalkyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl,optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10membered heterocyclyl)C₁₋₆alkyl, optionally substituted(C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted(5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy,C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

A is selected from the group consisting of C₃₋₇ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl, eachoptionally substituted by one or more R¹²;

R⁶ is selected from the group consisting of H, halogen, optionallysubstituted C₁₋₆ alkyl, OH, —C(O)OR, optionally substituted C₁₋₆ alkoxy,amino, N(OR⁸)R⁹, optionally substituted C₁₋₆ alkylthiol, C-amido,S-sulfonamido, CN, sulfinyl, sulfonyl, and a carboxylic acid isostere;

R is selected from the group consisting of H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3 to7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)O(3to 7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)C₆₋₁₀aryl, CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹C(O)NR¹³R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴, —CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄alkyl, —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄ alkyl,—CR¹⁰R¹¹OC(O)(CH₂)₁₋₃₀C(O)C₁₋₄ alkyl, and

R⁷ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹;

each R⁸ and R⁹ is independently selected from the group consisting of H,halogen, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹⁰ and R¹¹ is independently selected from the group consisting ofH, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹² is selected from the group consisting of hydrogen, amino, halogen,cyano, hydroxy, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₁₋₆ haloalkoxy, optionally substituted (C₁₋₆alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfhydryl,—C(O)(CH₂)₀₋₃SR^(e), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(e), —NR^(f)S(O)₂NR^(f)OR^(d), and—(CH₂)_(p)—Y⁶—(CH₂)_(q)K;

each R¹³ and R¹⁴ is independently selected from the group consisting ofH, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹⁵ is optionally substituted C₁₋₆ alkyl;

Y² is selected from the group consisting of —O—, —S—, and —NR⁹—;

Y³ is selected from the group consisting of —OH, —SH, and —NHR⁹;

Y⁴ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹; and

Y⁵ is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(g)—, or Y⁵ is absent;

Y⁶ is selected from the group consisting of —S—, —S(O)₂—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(f)—;

K is selected from the group consisting of C-amido; N-amido;S-sulfonamido; N-sulfonamido; —NR^(f)C(O)NR^(f)R^(g);—NR^(f)S(O)₂NR^(f)R^(g); —C(═NR^(e))R^(c); —C(═NR^(e))NR^(f)R^(g);—NR^(f)CR^(c)(═NR^(e)); —NR^(f)C(═NR^(e))NR^(f)R^(g); C₁₋₄ alkyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkoxy, amino, halogen, C-amido, and N-amido;C₆₋₁₀aryl optionally substituted with 0-2 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido,and N-amido; C₃₋₇ carbocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido; 5-10 membered heteroaryloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido, andN-amido; and 3-10 membered heterocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido;

each R^(c), R^(d), R^(e), R^(f), and R^(g) are independently selectedfrom the group consisting of H, halogen, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; and

each p and q is independently 0 or 1.

Some embodiments described herein relate to compounds having thestructure of the Formula III or IV, or pharmaceutically acceptable saltsthereof:

wherein (a)

each of R² and R³ is independently selected from the group consisting ofH, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S (O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d), or R² and R³ togetherwith the atoms to which they are attached form a fused ring or ringsystem selected from the group consisting of C₃₋₇carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, eachoptionally substituted with one or more R⁵;

m is an integer of 0 or 1; and

each R^(a) and R^(b) is independently selected from the group consistingof H, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d), or R^(a) and R^(b)together with the atoms to which they are attached form a spiro ring orring system selected from the group consisting of C₃₋₇carbocyclyl and3-10 membered heterocyclyl, each optionally substituted with one or moreR⁵; or (b)

m is 1;

R^(a) and R³ together with the atoms to which they are attached form afused ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵; and

each R² and R^(b) is independently selected from the group consisting ofH, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

R⁵ is —Y⁵—(CH₂)_(t)-G;

t is an integer of 0 or 1;

G is selected from the group consisting of H, amino, halogen, cyano,hydroxy, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆haloalkyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl,optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10membered heterocyclyl)C₁₋₆alkyl, optionally substituted(C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted(5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy,C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

A is a ring system selected from the group consisting of C₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10 memberedheteroaryl, each optionally substituted with one or more R¹²;

R⁶ is selected from the group consisting of H, halogen, optionallysubstituted C₁₋₆ alkyl, OH, —C(O)OR, optionally substituted C₁₋₆ alkoxy,amino, —N(OR⁸)R⁹, optionally substituted C₁₋₆ alkylthiol, C-amido,S-sulfonamido, CN, sulfinyl, sulfonyl, and a carboxylic acid isostere;

R is selected from the group consisting of H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3 to7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹(OC(O)OC₃₋₇carbocyclyl,—CR¹⁰R¹¹OC(O)O(3 to 7 membered heterocyclyl),—CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹C(O)NR₁₃R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴, —CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄alkyl, —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄alkyl,—CR¹⁰R¹¹OC(O)(CH₂)₁₋₃₀OC(O)C₁₋₄alkyl, and

R⁷ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹;

each R⁸ and R⁹ is independently selected from the group consisting of H,halogen, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹⁰ and R¹¹ is independently selected from the group consisting ofH, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹² is selected from the group consisting of hydrogen, amino, halogen,cyano, hydroxy, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₁₋₆ haloalkoxy, optionally substituted C₁₋₆alkylthiol, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, sulfhydryl, —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S(O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c),—NR^(f)S(O)₂NR^(f)OR^(d), and —(CH₂)_(p)—Y⁶—(CH₂)_(q)K;

each R¹³ and R¹⁴ is independently selected from the group consisting ofH, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹⁵ is optionally substituted C₁₋₆ alkyl;

Y² is selected from the group consisting of —O—, —S—, and —NR⁹—;

Y³ is selected from the group consisting of —OH, —SH, and —NHR⁹;

Y⁴ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹;

Y⁵ is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(g)—, or Y⁵ is absent;

Y⁶ is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(f)—;

K is selected from the group consisting of C-amido; N-amido;S-sulfonamido; N-sulfonamido; —NR^(f)C(O)NR^(f)R^(g);—NR^(f)S(O)₂NR^(f)R^(g); —C(═NR^(e))R^(c); —C(═NR^(e))NR^(f)R^(g);—NR^(f)CR^(c)(═NR^(e)); —NR^(f)C(═NR^(e))NR^(f)R^(g); C₁₋₄ alkyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkoxy, amino, halogen, C-amido, and N-amido;C₆₋₁₀aryl optionally substituted with 0-2 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido,and N-amido; C₃₋₇ carbocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido; 5-10 membered heteroaryloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido, andN-amido; and 3-10 membered heterocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido;

each R^(c), R^(d), R^(e), R^(f), and R^(g) are independently selectedfrom the group consisting of H, halogen, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; and

each p and q is independently 0 or 1.

Some further embodiments described herein relate to compounds having thestructure of the Formula V, or pharmaceutically acceptable salts thereof

wherein

Y¹ is N or CR⁴;

m is an integer of 0 or 1;

r is an integer of 0 or 1;

-   (a)

R² and R³ together with the atoms to which they are attached form afused ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl, each optionally substituted with one or more R⁵,and

each of R¹, R⁴, R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(C),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or

-   (b)

R³ and R⁴ together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R¹, R², R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or

-   (c)

R¹ and R² together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R³, R⁴, R^(a), and R^(b) is independently selected from thegroup consisting of H, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(C),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S (O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or

-   (d)

R^(a) and R^(b) together with the atoms to which they are attached forma spirocyclic ring or ring system selected from the group consisting ofC₃₋₇ carbocyclyl and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵, and

each of R¹, R², R³, and R⁴ is independently selected from the groupconsisting of H, amino, halogen, cyano, hydroxy, optionally substitutedC₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy,optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S(O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d); or

-   (e)

R^(a) and R⁴ together with the atoms to which they are attached form afused ring or ring system selected from the group consisting of C₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10 memberedheteroaryl, each optionally substituted with one or more R⁵, and

each of R¹, R², R³, and R^(b) is independently selected from the groupconsisting of H, amino, halogen, cyano, hydroxy, optionally substitutedC₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy,optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, optionally substituted(C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10 memberedheterocyclyl)C₁₋₆alkyl, optionally substituted (C₆₋₁₀aryl)C₁₋₆alkyl,(C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted (5-10 memberedheteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido,S-sulfonamido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S(O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d);

R⁵ is —Y⁵—(CH₂)_(t)-G;

t is an integer of 0 or 1;

G is selected from the group consisting of H, amino, halogen, cyano,hydroxy, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆haloalkyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆alkyl,optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10membered heterocyclyl)C₁₋₆alkyl, optionally substituted(C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted(5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy,C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

R⁶ is selected from the group consisting of optionally substituted—(CH₂)nC(O)OR and a carboxylic acid isostere;

n is an integer selected from 0 to 6;

R is selected from the group consisting of H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3 to7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)O(3to 7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)C₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹C(O)NR¹³R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴, —CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄alkyl, —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄alkyl,—CR¹⁰R¹¹OC(O)(CH₂)₁₋₃OC(O)C₁₋₄alkyl, and

R⁷ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹;

each R⁸ and R⁹ is independently selected from the group consisting of H,halogen, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹⁰and R¹¹ is independently selected from the group consisting ofH, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹³ and R¹⁴ is independently selected from the group consisting ofH, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹⁵ is optionally substituted C₁₋₆ alkyl;

Y² is selected from the group consisting of —O—, —S—, and —NR⁹—;

Y⁵ is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(g)—, or Y⁵ is absent;

each R^(c), R^(d), R^(e), R^(f), and R^(g) are independently selectedfrom the group consisting of H, halogen, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; and

each R^(h) and R^(i) is independently selected from the group consistingof H, halogen, cyano, amino, C-amido, N-amido, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; or R^(h)and R^(i) together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl, each optionally substituted with one or more R⁵.

Some embodiments described herein relate to compounds having thestructure of Formula VI, or pharmaceutically acceptable salts thereof:

wherein r is an integer of 0 or 1;

-   (a)

each of R² and R³ is independently selected from the group consisting ofH, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S (O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d), or R² and R³ togetherwith the atoms to which they are attached form a fused ring or ringsystem selected from the group consisting of C₃₋₇carbocyclyl and 3-10membered heterocyclyl, each optionally substituted with one or more R⁵;

m is an integer of 0 or 1;

each R^(a) and R^(b) is independently selected from the group consistingof H, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S (O)₂NR^(f)OR^(d), or R^(a) and R^(b)together with the atoms to which they are attached form a ring or ringsystem selected from the group consisting of C₃₋₇carbocyclyl, and 3-10membered heterocyclyl, each optionally substituted with one or more R⁵;or

-   (b)

m is 1;

R^(a) and R³ together with the atoms to which they are attached form aring or ring system selected from the group consisting ofC₃₋₇carbocyclyl, and 3-10 membered heterocyclyl, each optionallysubstituted with one or more R⁵; and

each R² and R^(b) is independently selected from the group consisting ofH, amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

R⁵ is —Y⁵—(CH₂)_(t)-G;

t is an integer of 0 or 1;

G is selected from the group consisting of H, amino, halogen, cyano,hydroxy, optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆haloalkyl, optionally substituted C₁₋₆ alkoxy, optionally substitutedC₁₋₆ haloalkoxy, optionally substituted (C₁₋₆ alkoxy)C₁₋₆ alkyl,optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionally substituted (3-10membered heterocyclyl)C₁₋₆alkyl, optionally substituted(C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C₁₋₆alkoxy, optionally substituted(5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy, O-carboxy,C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(c),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(═NR^(e)), —NR^(f)C(═NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d);

R⁶ is selected from the group consisting of optionally substituted—(CH₂)nC(O)OR and a carboxylic acid isostere;

n is an integer selected from 0 to 6;

R is selected from the group consisting of H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹(OC(O)C₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3to 7 membered heterocyclyl), —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹(OC(O)OC₃₋₇carbocyclyl,—CR¹⁰R¹¹OC(O)O(3 to 7 membered heterocyclyl),—CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹C(O)NR¹³R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴, —CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄alkyl, —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄alkyl,—CR¹⁰R¹¹OC(O)(CH₂)₁₋₃₀C(O)C₁₋₄ alkyl, and

R⁷ is selected from the group consisting of —OH, optionally substitutedC₁₋₆ alkoxy, amino, and —N(OR⁸)R⁹;

each R⁸ and R⁹ is independently selected from the group consisting of H,halogen, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹⁰and R¹¹ is independently selected from the group consisting ofH, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

each R¹³ and R¹⁴ is independently selected from the group consisting ofH, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl;

R¹⁵ is optionally substituted C₁₋₆ alkyl;

Y² is selected from the group consisting of —O—, —S—, and —NR⁹—;

Y⁵ is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR^(f)R^(g)—, and —NR^(g)—, or Y⁵ is absent;

each R^(c), R^(d), R^(e), R^(f), and R^(g) are independently selectedfrom the group consisting of H, halogen, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; and

each R^(h) and R^(i) is independently selected from the group consistingof H, halogen, cyano, amino, C-amido, N-amido, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 3-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; or R^(h)and R^(i) together with the atoms to which they are attached form aspirocyclic ring or ring system selected from the group consisting ofC₃₋₇ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl, each optionally substituted with one or more R⁵.

Some further embodiments described herein relate to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundhaving the structure of Formula I, II, III, IV, V or VI, as describedherein, or pharmaceutically acceptable salts thereof, and apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition may further comprise an additionalmedicament.

Some additional embodiments described herein relate to methods oftreating a bacterial infection comprising administering a compoundhaving the structure of Formula I, II, III, IV, V or VI as describedherein, or pharmaceutically acceptable salts thereof to a subject inneed thereof. In some embodiments, the method further comprisesadministering to the subject an additional medicament, for example, theadditional medicament may be selected from an antibacterial agent, anantifungal agent, an antiviral agent, an anti-inflammatory agent, or anantiallergic agent.

DETAILED DESCRIPTION OF EMBODIMENTS

Compounds of Formula I or II

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents. Various embodiments of these compounds includecompounds having the structures of Formula I or II as described above orpharmaceutically acceptable salts thereof. In some embodiments of thecompounds of Formula I or II, R is selected from H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

In some embodiments, the compounds of Formula I or II are alsorepresented by the structure of Formula Ia or IIa, or pharmaceuticallyacceptable salts thereof:

In some embodiments, the compounds of Formula Ia or IIa are alsorepresented by the structure of Formula Ib or IIb, or pharmaceuticallyacceptable salts thereof:

wherein each J, L, M is independently selected from CR¹² or N(nitrogen).

In some embodiments, m is 0 and the compounds of Formula Ib or IIb arealso represented by the structure of Formula Ic or IIc, orpharmaceutically acceptable salts thereof:

In some embodiments, the compounds of Formula Ic or IIc are in variousstereoisomeric form, including those represented by the structure ofFormula Ic-1, Ic-2, IIc-1 or IIc-2, or pharmaceutically acceptable saltsthereof:

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, II, IIa,IIb, or IIc, R² and R³ together with the atoms to which they areattached form a ring or ring system selected from the group consistingof C₃₋₇carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl, each optionally substituted with one or more R⁵. Insome such embodiments, R² and R³ together with the atoms to which theyare attached form C₃₋₇carbocyclyl optionally substituted with one ormore R⁵. In some further embodiments, wherein R² and R³ together withthe atoms to which they are attached form cyclopropyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tetrahydrofuranyl, ordihydrofuranyl, each optionally substituted with one or more R⁵. In someparticular embodiments, the compound of Formula Ic or IIc is alsorepresented by the structure of Formula Id or IId, or pharmaceuticallyacceptable salts thereof:

wherein the cyclopropyl moiety

is optionally substituted with one or more R⁵. In one embodiment,

is substituted with one R⁵. In another embodiment,

is substituted with two R⁵.

In some embodiments, the compounds of Formula Id or IId are in variousstereoisomeric forms, including those represented by the structure ofFormula Id-1, Id-2, IId-1 or IId-2, or pharmaceutically acceptable saltsthereof:

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, II,IIa, IIb, IIc or IId as described herein, R¹ is hydrogen. In anotherembodiment, R¹ is an optionally substituted C₁₋₆alkyl, for example, C₁₋₆hydroxyalkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, II,IIa, IIb, IIc or IId as described herein, R⁴ is hydrogen.

In some other embodiments of the compounds of Formula I, Ia, Ib, Ic, II,IIa, IIb, or IIc, R³ and R⁴ together with the atoms to which they areattached form a spiro ring or ring system selected from the groupconsisting of C₃₋₇carbocyclyl, and 3-10 membered heterocyclyl, eachoptionally substituted with one or more R⁵. In some such embodiments, R³and R⁴ together with the atoms to which they are attached formC₃₋₇carbocyclyl optionally substituted with one or more R⁵. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform cyclopropyl optionally substituted with one or more R⁵. In someother embodiments, R³ and R⁴ together with the atoms to which they areattached form 3-10 membered heterocyclyl optionally substituted with oneor more R⁵, for example, 3, 4, 5, 6, or 7 membered heterocyclylcomprising one, two or three heteroatoms selected from the groupconsisting of oxygen, nitrogen or sulfur. In some such embodiments, R¹is hydrogen. In some such embodiments, R² is hydrogen.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, II,IIa, IIb, IIc or IId as described herein, R⁶ is —C(O)OR. In some suchembodiments, R is H or C₁₋₉ alkyl. In some other embodiments, R is—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)c₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3 to7 membered heterocyclyl), or —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl. In some suchembodiments, the 3 to 7 membered heterocyclyl is

In some further embodiments, R is —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl,—CR¹⁰R¹¹OC(O)OC₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)O(3 to 7 memberedheterocyclyl), or —CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl. In some suchembodiments, the 3 to 7 membered heterocyclyl is

In still some further embodiments, R is CR¹⁰R¹¹C(O)NR¹³R¹⁴. In some suchembodiments, each of R¹³ and R¹⁴ is independently H or C₁₋₆ alkyl. Instill some further embodiments, R is —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴,CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄ alkyl, —CR¹⁰R¹¹OC(O)(CH₂)₁₋₃₀C(O)C₁₋₄alkyl, or —CR¹⁰R¹¹K OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄ alkyl. In some embodiments,each R¹⁰and R¹¹ is independently hydrogen or C₁₋₆ alkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, II,IIa, IIb, IIc or IId as described herein, R⁷ is —OH.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, or Id asdescribed herein, Y² is —O—.

In some embodiments of the compounds of Formula II, IIa, IIb, IIc or IIdas described herein, Y³ is —OH. In some embodiments, Y⁴ is —OH.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, II,IIa, IIb, IIc or IId as described herein, Y⁵ is absent and t is 0, andR⁵ is selected from the group consisting of amino, halogen, cyano,hydroxy, optionally substituted C₁₋₆ alkoxy, acyl, C-carboxy, C-amido,N-amido, N-sulfonamido, —SR^(c), —C(O)(CH₂)₀₋₃SR^(c),—C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g), —NR^(f)S(O)₂NR^(f)R^(g),—C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g), —NR^(f)CR^(c)(═NR^(e)),—NR^(f)C(═NR^(e))NR^(f)R^(g), —S(O)(CH₂)₁₋₃R^(c), and—NR^(f)S(O)₂NR^(f)OR^(d). In one embodiment, R⁵ is halogen.

In some embodiments of the compounds of Formula Ib, Ic, Id, IIb, IIc, orIId as described herein, each J, L and M is CR¹². In some suchembodiments, R¹² is hydrogen, halogen, C₁₋₆ alkoxy, or C₁₋₆ haloalkoxy.In some other embodiments, at least one of J, L and M of Formula Ib, Ic,Id, IIb, IIc, or IId is N (nitrogen). In one such embodiment, M isnitrogen.

In some embodiments, the compounds of Formula I or II as describedherein are selected from the group consisting of

of Table 1, and pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutically acceptable salts are selectedfrom alkaline metal salts or ammonium salts. In one embodiment, thepharmaceutically acceptable salts are sodium salts with the structuresselected from the group consisting of:

Compounds of Formula III or IV

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents. Various embodiments of these compounds includecompounds having the structures of Formula III or IV as described aboveor pharmaceutically acceptable salts thereof. In some embodiments of thecompounds of Formula III or IV, R is selected from H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

In some embodiments, the compounds of Formula III or IV are alsorepresented by the structure of Formula Ma or IVa, or pharmaceuticallyacceptable salts thereof:

wherein each J, L, M is independently selected from CR¹² or N(nitrogen).

In some embodiments, m is 0 and the compounds of Formula IIIa or IVa arealso represented by the structure of Formula IIIb or IVb, orpharmaceutically acceptable salts thereof:

In some embodiments of the compounds of Formula III, IIa, IIb, IV, IVa,or IVb as described herein, R² is selected from H, halogen, or C₁₋₆alkyl.

In some embodiments of the compounds of Formula III, IIIa, IIIb, IV,IVa, or IVb as described herein, R³ is hydrogen.

In some other embodiments of the compounds of Formula III, IIIa, IIIb,IV, IVa, or IVb as described herein, R² and R³ together with the atomsto which they are attached form a fused ring or ring system selectedfrom the group consisting of C₃₋₇carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl, each optionallysubstituted with one or more R⁵. In some such embodiments, R² and R³together with the atoms to which they are attached form C₃₋₇carbocyclyloptionally substituted with one or more R⁵. In one embodiment, R² and R³together with the atoms to which they are attached form cyclopropyloptionally substituted with one or more R⁵.

In some embodiments of the compounds of Formula III, IIa, IIIb, IV, IVa,or IVb as described herein, R⁶ is —C(O)OR. In some such embodiments, Ris H or C₁₋₉ alkyl. In some other embodiments, R is—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)(3 to7 membered heterocyclyl), or —CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl. In some suchembodiments, the 3 to 7 membered heterocyclyl is

In some further embodiments, R is —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl,—CR¹⁰R¹¹(OC(O)OC₃₋₇carbocyclyl, —CR¹⁰R¹¹OC(O)O(3 to 7 memberedheterocyclyl), or —CR¹⁰R¹¹OC(O)OC₂₋₈alkoxyalkyl. In some suchembodiments, the 3 to 7 membered heterocyclyl is

In still some further embodiments, R is CR¹⁰R¹¹C(O)NR¹³R¹⁴. In some suchembodiments, each of R¹³ and R¹⁴ is independently H or C₁₋₆ alkyl. Instill some further embodiments, R is —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄ alkyl, —CR¹⁰R¹¹OC(O)(CH₂)₁₋₃OC(O)C₁₋₄alkyl, or —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄ alkyl. In some embodiments,each R¹⁰ and R¹¹ is independently hydrogen or C₁₋₆ alkyl.

In some embodiments of the compounds of Formula III, IIa, IIb, IV, IVa,or IVb as described herein, R⁷ is —OH.

In some embodiments of the compounds of Formula III, IIa, or IIIb asdescribed herein, Y² is —O—.

In some embodiments of the compounds of Formula IV, IVa, or IVb asdescribed herein, Y³ is —OH. In some embodiments, Y⁴ is —OH.

In some embodiments of the compounds of Formula IIa, IIb, IVa, or IVb asdescribed herein, each J, L and M is CR¹². In some such embodiments, R¹²is selected from hydrogen, halogen or C₁₋₆ alkoxy. In some otherembodiments, at least one of J, L and M is N (nitrogen). In oneembodiments, M is N.

In some embodiments, the compounds of Formula III or IV are selectedfrom the group consisting of

of Table 1, or pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutically acceptable salts are selectedfrom alkaline metal salts or ammonium salts. In one embodiment, thepharmaceutically acceptable salts are sodium salts.

Compounds of Formula V

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents. Various embodiments of these compounds includecompounds having the structures of Formula V as described above orpharmaceutically acceptable salts thereof. In some embodiments of thecompounds of Formula V, R is selected from H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

In some embodiments, the compounds of Formula V are also represented bythe structure of Formula Va, or pharmaceutically acceptable saltsthereof:

In some embodiments, m is 1 and the compounds of Formula Va are alsorepresented by the structure of Formula Vb, or pharmaceuticallyacceptable salts thereof:

In some embodiments of the compounds of the Formula V, Va or Vb, bothR^(a) and R^(b) are H.

In some embodiments of the compounds of the Formula V, Va or Vb asdescribed herein, R² and R³ together with the atoms to which they areattached form a fused ring or ring system selected from the groupconsisting of C₃₋₇ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀aryl,and 5-10 membered heteroaryl, each optionally substituted with one ormore R⁵. In some such embodiments, R² and R³ together with the atoms towhich they are attached form C₃₋₇carbocyclyl optionally substituted withone or more R⁵. In one embodiment, R² and R³ together with the atoms towhich they are attached form cyclopropyl optionally substituted with oneor more R⁵.

In some embodiments of the compounds of the Formula V, Va or Vb asdescribed herein, r is 1, and both R^(h) and R^(i) are H.

In some embodiments of the compounds of the Formula V, Va or Vb asdescribed herein, R⁶ is —(CH₂)nC(O)OR and n is 0. In some suchembodiment, the compound is also represented by the structure of FormulaVc or pharmaceutically acceptable salts thereof:

wherein the cyclopropyl moiety

is optionally substituted with one or more R⁵. In one example,

is substituted with one R⁵ and the compound is also represented by thestructure of Formula Vd:

In some embodiments, the compounds of Formula Vc are in variousstereoisomeric forms, including those represented by the structure ofFormula Vc-1 or Vc-2, or pharmaceutically acceptable salts thereof:

In some embodiments of the compounds of Formula V, Va, Vb or Vc asdescribed herein, R⁷ is —OH.

In some embodiments of the compounds of Formula V, Va, Vb or Vc asdescribed herein, Y² is —O—.

Compounds of Formula VI

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents. Various embodiments of these compounds includecompounds having the structures of Formula VI as described above orpharmaceutically acceptable salts thereof. In some embodiments of thecompounds of Formula VI, R is selected from H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

In some embodiments, m is 1 and the compounds of Formula VI are alsorepresented by the structure of Formula VIa, or pharmaceuticallyacceptable salts thereof:

In some embodiments of the compounds of Formula VI or VIa, both R^(a)and R^(b) are H.

In some embodiments of the compounds of Formula VI or VIa, r is 1, andboth R^(h) and R^(i) are H.

In some embodiments of the compounds of the Formula VI or VIa asdescribed herein, R⁶ is —(CH₂)nC(O)OR and n is 0. In some suchembodiment, the compound is also represented by the structure of FormulaVIb or pharmaceutically acceptable salts thereof:

In some embodiments of the compounds of Formula VI, VIa, or VIb asdescribed herein, R⁷ is —OH.

In some embodiments of the compounds of Formula VI, VIa, or VIb asdescribed herein, Y² is —O—.

Exemplary compounds described herein are illustrated in Table 1 below.

TABLE 1 Compd # Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

In some embodiments, the pharmaceutically acceptable salts are selectedfrom alkaline metal salts or ammonium salts. In one embodiment, thepharmaceutically acceptable salts are sodium salts, including disodiumsalts.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

In some embodiments, due to the facile exchange of boron esters, thecompounds described herein may convert to or exist in equilibrium withalternate forms. Accordingly, in some embodiments, the compoundsdescribed herein may exist in combination with one or more of theseforms. For example, as shown below, the compounds disclosed herein mayexist in cyclic boronate monoesters with the structure of Formulae I,Ia, Ib, Ic, and Id or in acyclic form as boronic acids with thestructure of Formulae II, IIa, IIb, IIc, IId, or may exist as a mixtureof the two forms depending on the medium. In some embodiments, thecompounds disclosed herein may exist in cyclic form as cyclic boronatemonoesters with the structure of Formulae III, IIa, and IIIb or inacyclic form as boronic acids with the structure of Formulae IV, IVa andIVb, or may exist as a mixture of the two forms depending on the medium.Exemplary equilibrium equation between the cyclic boronate monoestersand the acyclic form boronic acids are demonstrated below:

In some embodiments, the compounds described herein may exist in cyclicdimeric form, trimeric form or tetrameric form. For example, thecompound of Formula II may exist in dimeric form (II-A), trimeric form(II-B), or tetrameric form (II-C):

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. As used in this specification, whether in a transitionalphrase or in the body of the claim, the terms “comprise(s)” and“comprising” are to be interpreted as having an open-ended meaning. Thatis, the terms are to be interpreted synonymously with the phrases“having at least” or “including at least.” When used in the context of aprocess, the term “comprising” means that the process includes at leastthe recited steps, but may include additional steps. When used in thecontext of a compound, composition, or device, the term “comprising”means that the compound, composition, or device includes at least therecited features or components, but may also include additional featuresor components.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

As used herein, common organic abbreviations are defined as follows:

Ac Acetyl

aq. Aqueous

Bn Benzyl

Bz Benzoyl

BOC or Boc tert-Butoxycarbonyl

° C. Temperature in degrees Centigrade

DCM Dichloromethane

DMF N,N-dimethylformamide

EA Ethyl acetate

ESBL Extended-spectrum β-lactamase

Et Ethyl

g Gram(s)

h or hr Hour(s)

HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

iPr Isopropyl

m or min Minute(s)

MECN Acetonitrile

mL Milliliter(s)

NMR Nuclear magnetic resonance

PE Petroleum ether

PG Protecting group

Ph Phenyl

rt Room temperature

TBDMSCl tert-Butyldimethylsilyl chloride

TBS tert-Butyldimethylsilyl

Tert, t tertiary

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin-layer chromatography

μL Microliter(s)

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

The term “halogen” or “halo,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that is fully saturated (i.e., contains no double or triplebonds). The alkyl group may have 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group may bedesignated as “C₁₋₄ alkyl” or similar designations. By way of exampleonly, “C₁₋₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, and the like.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylas is defined above, such as “C₁₋₉ alkoxy”, including but not limited tomethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” refers to the formula SR wherein R is analkyl as is defined above, such as “C₁₋₉ alkylthio” and the like,including but not limited to methylmercapto, ethylmercapto,n-propylmercapto, 1-methylethylmercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group may be designated as “C₂₋₄ alkenyl” orsimilar designations. By way of example only, “C₂₋4 alkenyl” indicatesthat there are two to four carbon atoms in the alkenyl chain, i.e., thealkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten- 1-yl, buten-2-yl, buten-3-yl,buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groupsinclude, but are in no way limited to, ethenyl, propenyl, butenyl,pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group may be designated as “C₂₋₄ alkynyl” orsimilar designations. By way of example only, “C₂₋₄ alkynyl” indicatesthat there are two to four carbon atoms in the alkynyl chain, i.e., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn- 1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Typical alkynyl groups include, but are in no way limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

As used herein, “heteroalkyl” refers to a straight or branchedhydrocarbon chain containing one or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur, in the chain backbone. The heteroalkyl group may have1 to 20 carbon atom, although the present definition also covers theoccurrence of the term “heteroalkyl” where no numerical range isdesignated. The heteroalkyl group may also be a medium size heteroalkylhaving 1 to 9 carbon atoms. The heteroalkyl group could also be a lowerheteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group may bedesignated as “C₁₋₄ heteroalkyl” or similar designations. Theheteroalkyl group may contain one or more heteroatoms. By way of exampleonly, “C₁₋₄ heteroalkyl” indicates that there are one to four carbonatoms in the heteroalkyl chain and additionally one or more heteroatomsin the backbone of the chain.

As used herein, “alkylene” means a branched, or straight chain fullysaturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). The alkylene group may have 1 to 20carbon atoms, although the present definition also covers the occurrenceof the term alkylene where no numerical range is designated. Thealkylene group may also be a medium size alkylene having 1 to 9 carbonatoms. The alkylene group could also be a lower alkylene having 1 to 4carbon atoms. The alkylene group may be designated as “C₁₋₄ alkylene” orsimilar designations. By way of example only, “C₁₋₄ alkylene” indicatesthat there are one to four carbon atoms in the alkylene chain, i.e., thealkylene chain is selected from the group consisting of methylene,ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl,1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene,1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, “alkenylene” means a straight or branched chaindi-radical chemical group containing only carbon and hydrogen andcontaining at least one carbon-carbon double bond that is attached tothe rest of the molecule via two points of attachment. The alkenylenegroup may have 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term alkenylene where no numericalrange is designated. The alkenylene group may also be a medium sizealkenylene having 2 to 9 carbon atoms. The alkenylene group could alsobe a lower alkenylene having 2 to 4 carbon atoms. The alkenylene groupmay be designated as “C₂₋₄ alkenylene” or similar designations. By wayof example only, “C₂₋₄ alkenylene” indicates that there are two to fourcarbon atoms in the alkenylene chain, i.e., the alkenylene chain isselected from the group consisting of ethenylene, ethen- 1,1-diyl,propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene,but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl,but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl,1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl,1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene,2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl,and 2,2-dimethyl-ethen- 1,1-diyl.

The term “aromatic” refers to a ring or ring system having a conjugatedpi electron system and includes both carbocyclic aromatic (e.g., phenyl)and heterocyclic aromatic groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, “aryl” refers to an aromatic ring or ring system (i.e.,two or more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. The aryl group may have 6 to 18 carbonatoms, although the present definition also covers the occurrence of theterm “aryl” where no numerical range is designated. In some embodiments,the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C₆₋₁₀aryl,” “C₆ or C₁₀ aryl,” or similar designations.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, azulenyl, and anthracenyl.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl as is defined above, such as “C₆₋₁₀aryloxy” or“C₆₋₁₀arylthio” and the like, including but not limited to phenyloxy.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group, such as “C₇₋₁₄ aralkyl” and thelike, including but not limited to benzyl, 2-phenylethyl,3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group isa lower alkylene group (i.e., a C₁₋₄ alkylene group).

As used herein, “heteroaryl” refers to an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. The heteroaryl group may have 5-18 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heteroaryl” where no numerical range isdesignated. In some embodiments, the heteroaryl group has 5 to 10 ringmembers or 5 to 7 ring members. The heteroaryl group may be designatedas “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similardesignations. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, and benzothienyl.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. Insome cases, the alkylene group is a lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ringsystem containing only carbon atoms in the ring system backbone. Whenthe carbocyclyl is a ring system, two or more rings may be joinedtogether in a fused, bridged or spiro-connected fashion. Carbocyclylsmay have any degree of saturation provided that at least one ring in aring system is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20carbon atoms, although the present definition also covers the occurrenceof the term “carbocyclyl” where no numerical range is designated. Thecarbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3to 6 carbon atoms. The carbocyclyl group may be designated as “C₃₋₆carbocyclyl” or similar designations. Examples of carbocyclyl ringsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl,adamantyl, and spiro[4.4]nonanyl.

A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as asubstituent, via an alkylene group, such as “C₄₋₁₀ (carbocyclyl)alkyl”and the like, including but not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. Insome cases, the alkylene group is a lower alkylene group.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” means a carbocyclyl ring or ring systemhaving at least one double bond, wherein no ring in the ring system isaromatic. An example is cyclohexenyl.

As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ringsystem containing at least one heteroatom in the ring backbone.Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. The heterocyclyl group may have 3 to 20 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heterocyclyl” where no numerical range isdesignated. The heterocyclyl group may also be a medium sizeheterocyclyl having 3 to 10 ring members. The heterocyclyl group couldalso be a heterocyclyl having 3 to 6 ring members. The heterocyclylgroup may be designated as “3-6 membered heterocyclyl” or similardesignations. In preferred six membered monocyclic heterocyclyls, theheteroatom(s) are selected from one up to three of O, N or S, and inpreferred five membered monocyclic heterocyclyls, the heteroatom(s) areselected from one or two heteroatoms selected from O, N, or S. Examplesof heterocyclyl rings include, but are not limited to, azepinyl,acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline.

A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as asubstituent, via an alkylene group. Examples include, but are notlimited to, imidazolinylmethyl and indolinylethyl.

As used herein, “acyl” refers to —C(═O)R, wherein R is selected fromhydrogen, optionally substituted C₁₋₆ alkyl, halogen, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, optionally substituted C₁₋₆ alkyl, halogen, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, halogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein. Anon-limiting example includes carboxyl (i.e., —C(═O)OH).

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is selectedfrom hydrogen, optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted C₆₋₁₀aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl, as defined herein.

A “sulfonyl” group refers to an “—SO₂R” group in which R is selectedfrom hydrogen, optionally substituted C₁₋₆ alkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted C₆₋₁₀aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl, as defined herein.

An “S-sulfonamido” group refers to a “—SO₂NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein.

An “N-sulfonamido” group refers to a “—N(R_(A))SO₂R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, and optionally substituted 3-10 memberedheterocyclyl, as defined herein.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) are each independently selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein.

An “N-amido” group refers to a “—N(R_(A))C(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, halogen,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, andoptionally substituted 3-10 membered heterocyclyl, as defined herein.

An “O-carbamyl” group refers to a “—OC(═O)NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-carbamyl” group refers to an “—N(R_(A))OC(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-thiocarbamyl” group refers to a “—OC(═S)NR_(A)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ ryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

An “N-thiocarbamyl” group refers to an “—N(R_(A))OC(═S)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, halogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted C₆₋₁₀aryl, optionally substituted 5-10 memberedheteroaryl, and optionally substituted 3-10 membered heterocyclyl asdefined herein. A non-limiting example includes free amino (i.e., —NH₂).

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈ alkoxyalkyl” and the like.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substituents independently selected fromC₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 3-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 3-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF₃), halo(C₁-C₆)alkoxy(e.g., OCF3), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl,nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O). Wherever a group is described as “optionally substituted”that group can be substituted with the above substituents.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂, —CH₂CH₂,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

When two R groups are said to form a ring (e.g., a carbocyclyl,heterocyclyl, aryl, or heteroaryl ring) “together with the atom to whichthey are attached,” it is meant that the collective unit of the atom andthe two R groups are the recited ring. The ring is not otherwise limitedby the definition of each R group when taken individually. For example,when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the nitrogen to whichthey are attached form a heterocyclyl, it is meant that R¹ and R² can beselected from hydrogen or alkyl, or alternatively, the substructure hasstructure:

where ring A is a heteroaryl ring containing the depicted nitrogen.

Similarly, when two “adjacent” R groups are said to form a ring“together with the atom to which they are attached,” it is meant thatthe collective unit of the atoms, intervening bonds, and the two Rgroups are the recited ring. For example, when the followingsubstructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the atoms to which theyare attached form an aryl or carbocylyl, it is meant that R¹ and R² canbe selected from hydrogen or alkyl, or alternatively, the substructurehas structure:

where A is an aryl ring or a carbocylyl containing the depicted doublebond.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

As used herein, “isosteres” of a chemical group are other chemicalgroups that exhibit the same or similar properties. For example,tetrazole is an isostere of carboxylic acid because it mimics theproperties of carboxylic acid even though they both have very differentmolecular formulae. Tetrazole is one of many possible isostericreplacements for carboxylic acid. Other carboxylic acid isosterescontemplated include —SO₃H, —SO₂HNR, —PO₂(R)₂, —PO₃(R)₂, —CONHNHSO₂R,—COHNSO₂R, and —CONRCN, where R is selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocyclyl, as defined herein. Inaddition, carboxylic acid isosteres can include 5-7 membered carbocyclesor heterocycles containing any combination of CH₂, O, S, or N in anychemically stable oxidation state, where any of the atoms of said ringstructure are optionally substituted in one or more positions. Thefollowing structures are non-limiting examples of carbocyclic andheterocyclic isosteres contemplated. The atoms of said ring structuremay be optionally substituted at one or more positions with R as definedabove.

It is also contemplated that when chemical substituents are added to acarboxylic isostere, the compound retains the properties of a carboxylicisostere. It is contemplated that when a carboxylic isostere isoptionally substituted with one or more moieties selected from R asdefined above, then the substitution and substitution position isselected such that it does not eliminate the carboxylic acid isostericproperties of the compound. Similarly, it is also contemplated that theplacement of one or more R substituents upon a carbocyclic orheterocyclic carboxylic acid isostere is not a substitution at one ormore atom(s) that maintain(s) or is/are integral to the carboxylic acidisosteric properties of the compound, if such substituent(s) woulddestroy the carboxylic acid isosteric properties of the compound.

Other carboxylic acid isosteres not specifically exemplified in thisspecification are also contemplated.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes, but is not limited to, primates, includingsimians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep,goats, swine, rabbits, dogs, cats, rodents, rats, mice guinea pigs, orthe like.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. In addition, various adjuvants such as are commonly usedin the art may be included. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 8th Ed., Pergamon Press.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of a disease or condition, and includes curing a disease orcondition. “Curing” means that the symptoms of a disease or conditionare eliminated; however, certain long-term or permanent effects mayexist even after a cure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition to a subject forprophylactic and/or therapeutic purposes. The term “prophylactictreatment” refers to treating a subject who does not yet exhibitsymptoms of a disease or condition, but who is susceptible to, orotherwise at risk of, a particular disease or condition, whereby thetreatment reduces the likelihood that the patient will develop thedisease or condition. The term “therapeutic treatment” refers toadministering treatment to a subject already suffering from a disease orcondition.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, (ed. H.Bundgaard, Elsevier, 1985), which is hereby incorporated herein byreference in its entirety.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivoyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of pro-drug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); and“Bioreversible Carriers in Drug Design: Theory and Application”, editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providingexamples of esters useful as prodrugs for compounds containing carboxylgroups). Each of the above-mentioned references is herein incorporatedby reference in their entirety.

“Metabolites” of the compounds disclosed herein include active speciesthat are produced upon introduction of the compounds into the biologicalmilieu.

“Solvate” refers to the compound formed by the interaction of a solventand a compound described herein, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of a compound, which are notbiologically or otherwise undesirable for use in a pharmaceutical. Inmany cases, the compounds herein are capable of forming acid and/or basesalts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, as described in WO 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein in itsentirety). Some examples of pharmaceutically acceptable base additionsalts of the compounds disclosed herein have the structure of FormulaI′, Ia′, Ib′, Ic′, Id′, II′, IIa′, IIb′, IIc′ or IId′:

wherein each of Z⊕ and R may be independently selected from an alkalimetal cation or an ammodium cation (NH₄ ⁺).

Some other examples of pharmaceutically acceptable base addition saltsof the compounds described herein have the structure of Formula III′,IIIa′, IIIb′, IV′, IVa′, or IVb′:

wherein each of Z⊕ and R may be indpendently selected from an alkalimetal cation or an ammodium cation (NH₄ ⁺).

Some other examples of pharmaceutically acceptable base addition saltsof the compounds described herein have the structure of Formula V′, Va′,Vb′ or Vc′:

wherein each of Z⊕ and R may be indpendently an alkali metal cation oran ammodium cation (NH₄ ⁺).Methods of Preparation

The compounds disclosed herein may be synthesized by methods describedbelow, or by modification of these methods. Ways of modifying themethodology include, among others, temperature, solvent, reagents etc.,known to those skilled in the art. In general, during any of theprocesses for preparation of the compounds disclosed herein, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973);and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis(3rd ed.) Wiley, N.Y. (1999), which are both hereby incorporated hereinby reference in their entirety. The protecting groups may be removed ata convenient subsequent stage using methods known from the art.Synthetic chemistry transformations useful in synthesizing applicablecompounds are known in the art and include e.g. those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, orL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons, 1995, which are both hereby incorporated herein byreference in their entirety. The routes shown and described herein areillustrative only and are not intended, nor are they to be construed, tolimit the scope of the claims in any manner whatsoever. Those skilled inthe art will be able to recognize modifications of the disclosedsyntheses and to devise alternate routes based on the disclosuresherein; all such modifications and alternate routes are within the scopeof the claims.

In the following schemes, protecting groups for oxygen atoms areselected for their compatibility with the requisite synthetic steps aswell as compatibility of the introduction and deprotection steps withthe overall synthetic schemes (P. G. M. Green, T. W. Wutts, ProtectingGroups in Organic Synthesis (3rd ed.) Wiley, N.Y. (1999)). Handling ofprotecting and/or sterodirecting groups specific to boronic acidderivatives is described in a recent review of chemistry of boronicacids: D. G. Hall (Ed.), Boronic Acids. Preparation and Application inOrganic Synthesis and Medicine, Wiley VCH (2005) and in earlier reviews:Matteson, D. S. (1988). Asymmetric synthesis with boronic esters.Accounts of Chemical Research, 21(8), 294-300, and Matteson, D. S.(1989). Tetrahedron, 45(7), 1859-1885), all of which are incorporatedherein by reference in their entirety. The latter review articles alsodescribe methodology for stereoselective insertion of halomethinefunctionality next to the boronate which is employed in the syntheticschemes below.

In addition to standard acid catalyzed deprotection, special methods forremoval of boronic acid protecting and/or sterodirecting groups methodsusing fluorides (Yuen, A. K. L., & Hutton, C. A. (2005). TetrahedronLetters, 46(46), 7899-7903, which isincorporated herein by reference inits entirety) or periodate oxidation (Coutts, S. J., et al. (1994).Tetrahedron Letters, 35(29), 5109-5112, which is incorporated herein byreference in its entirety) can also be employed in preparations of thecompounds disclosed herein.

In strategies employing pinanediol or other diol-based chiralauxiliaries for stereospecific introduction of new chiral centers, theearly stages of chemistry on boronic intermediates can be performed onchiral boronate esters or alternatively nonchiral borate/boronateintermediates can be used in early stages followed bytransesterification with chiral diols prior to the step wherestereoselection is required.

Exemplary Synthetic Schemes for the Preparation of Compounds of FormulaeI, III and V

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds encompassed herein. Furthermore, other methods for preparingcompounds described herein will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. Unless otherwise indicated, all variables are as definedabove.

Compounds of formula IX (embodiments of the compound of Formula I) whereR is H can be prepared as depicted in Schemes 1-4 from key intermediatesI-3, II-5, III-3 and IV-1, which may be assembled by known reactions(Boronic Acids: Preparations and Applications in Organic Synthesis,Medicine and Materials, D. G. Hall, ed., Wiley-VCH, Weinheim, 2011,which is incorporated herein by reference in its entirety).

Compounds of formula IX can be made starting from protected aryl orheteroaryl precursors of formula I-1 via Z-vinyl boronate (I-3) followedby cyclopropanation and deprotection. The compounds of formula I-3 maybe attained from 1-2 (where X is halogen), which may be made by means ofknown methods of Z-haloalkene formation (Tetrahedron Lett., 2001, 42,3893-3896) with conventional protecting groups for R′, R″, and R′″, suchas those described in Protective Groups in Organic Chemistry (ed. J. F.W. McOmie, Plenum, 1973, which is incorporated herein by reference inits entirety); and Protecting Groups in Organic Synthesis P. G. M.Wutts, T. W. Green, Wiley, N.Y., 1999, which is incorporated herein byreference in its entirety). Aryl compounds of formula I-2 uponborylation by well-known available methods (Chem. Rev. 2010, 110,890-931, which is incorporated herein by reference in its entirety) andboronate ester formation with desired chiral auxiliary giveintermediates of formula I-3. Alternatively vinyl boronate derivativeI-3 can also be made via acetylene derivative of formula I-5, which canbe made from compounds of formula I-1 by acetylene coupling such as inSonogoshira reaction. Phenyl acetylene derivatives of formula I-5 can betransformed into Z-vinylboronates (I-3) by ruthenium hydride pincercomplex catalysed addition of pinacolborane to terminal alkynes. (J. Am.Chem. Soc., 2012, 134, 14349-14352). A Cu-catalysed Z-selectivehydroboration of alkynes with 1,8-diaminonaphthaleneborane may also beutilized to make compounds of formula I-3 from terminal alkynes (I-5)(Org. Lett., 2016, 18, 1390-1393). Terminal acetylenes of formula I-5can be selectively transformed under silver catalyzed hydroborationconditions to compounds of formula I-6 (Tetrahedron, 2014, 70,5815-5819). Such alkynyl boronates of formula I-6 can be reducedstereoselectively to the cis-alkenyl pinacolboronates (I-3) viahydroboration with dicyclohexylborane (J. Org. Chem., 2008, 73,6841-6844).

Cyclopropanation of compounds of formula I-3 to I-4 may be attained bypalladium or Zn mediated carbene additions (J. Am. Chem. Soc., 2015,137, 13176-13182). Such transformations can also be done to givecompounds of 1-4 in high enantioselectivity (Tetrahedron, 2008, 64,7041-7095; Eur. J. Org. Chem. 2000, 2557-2562). Alternatively,dimethyloxosulfonium methylide also reacts with enones to undergo1,4-addition followed by ring closure to give a cyclopropane derivatives(Tetrahedron Lett., 2003, 44, 3629-3630). A phosphate carbenoid(RO)₂P(O)OZnCH₂I (J. Org. Chem., 2010, 75, 1244-1250; Org. Process Res.Dev., 2016, 20, 786-798) that can be stored may be utilized in suchcyclopropanations from I-3 to I-4. Iodonium ylides derived from malonatemethyl ester may also be utilized for higher reactivity in the Rhcatalyzed cyclopropanation (Org. Lett., 2012, 14, 317-3173).

Simultaneous deprotection of pinane ester and salicylic acid protectivegroups of compounds of formula I-4 can be achieved by treating withdilute HCl or trifluoroacetic acid, affording the desired compounds ofstructure IX. This transformation may also be achieved by treatment withBCl₃ or BBr₃ as disclosed in WO 2009/064414, which is incorporatedherein by reference in its entirety. Alternatively, the deprotection maybe attained via trans-esterification with isobutyl boronic acid inpresence of dilute acid (as disclosed in WO 2009/064413, which isincorporated herein by reference in its entirety) or via other knownmethods (J. Org. Chem. (2010), 75, 468-471, which is incorporated hereinby reference in its entirety). A two-step procedure for deprotection ofalkylpinacolylboronate esters is also known via transesterification withdiethanolamine followed by hydrolysis (J. Org. Chem., 2011, 76,3571-3575). Compounds of formula I-4 where Z is DAN(1,8-diaminonaphthalene) protected boramide may be deprotected utilizingmild acidic conditions (J. Am. Chem. Soc. 2007, 129, 758-759)

In an alternative sequence, compounds of formula IX can be made via aconvergent approach from intermediates II-3 and II-4 as shown in Scheme2. Salicylic acid derivatives of formula II-4 where Y is a leaving groupundergo coupling reaction with Reformatsky reagent of II-3 in Negishiconditions to give intermediates of formula II-5 (Tetrahedron, 2014,1508-1515; J. Org. Chem., 2013, 78, 8250-8266, each of which isincorporated herein by reference in its entirety). Intermediates offormula II-4 where Y is —B(OH)₂ undergo palladium mediated Suzuki typecross-coupling with II-3 (J. Org. Chem., 1996, 61, 8718-8719) to givecompounds of formula II-5. Intermediates of 11-3 can be made bydecarboxylation of II-2 (the preparation of which is disclosed in WO2011154953), which in turn may be made from corresponding carboxylicacid via C-H insertion (Angew. Chem. Int. Ed., 2016, 55, 785-789), orvia Simmons-Smith reaction of cis-vinyl boronate precursors (Eur. J.Org. Chem. 2000, 2557-2562). Intermediates of formula II-5 can befurther transformed to compound of formula IX under the conditionsdescribed in scheme 1.

In another example, compounds of formula XI (embodiments of the compoundof Formula V) can be made via borylation followed by cyclopropanationfrom acetylene intermediate III-2 as shown in Scheme 3. Alcohols offormula III-1 can be made by a variety of ways known in literature inboth chiral forms. Such protected alcohols of III-1 may be made byselective reduction of diketones to give 3,5-dihydroxypentanoate (m=1)(J. Org. Chem., 2000, 65, 7792-7799) or 3,6-dihydroxypentanoate (m=2)(Org. Biomol. Chem., 2011, 9, 4823-4830) intermediates. Acetyleneintermediates of formula III-2 can be made from oxidation ofintermediates of III-1 followed by Corey-Fuchs method (Org. Synth. 2005,81, 1). Alternatively, aldehydes of III-1 can also be transformed toIII-2 by treating with dimethyl-1-(1-diazo-2-oxopropyl)phosphonate (J.Am. Chem. Soc., 2003, 125, 3714-3715). Such acetylene intermediates ofIII-2 can be further converted to compounds of XI via borylation,cyclopropanation and deprotection sequence as described above in Scheme1.

Compounds of formula IV-2 (embodiments of compounds of Formula III),IV-4 (embodiments of compounds of Formula I), and IV-6 (embodiments ofcompounds of Formula I), may be prepared from appropriately protectedvinyl boronate intermediates of formula IV-1 (prepared in Scheme 1) asshown in Scheme 4. Derivatives of formula IV-1 can be directlytransformed to vinyl boronates of IV-2 by deprotection in the conditionsdescribed above in scheme 1. Intermediates of formula IV-1 may betreated with diazoacetates (Tetrahedron, 2008, 64, 7041-7095) to undergocyclopropanation followed by selective ester deprotection to carboxylicacid intermediates of formula IV-3. Such carboxylic acids undergo amideformation followed by deprotection to give amide analogs of formulaINT-4 (Org. Process Res. Dev., 2016, 20, 140-177). The carboxylic acidsof IV-3 may be converted to carbamates (IV-5) via Curtius rearrangement(Chem. Rev. 1988, 88, 297-368; Org. Lett., 2005, 4107-4110; Eur. J. Org.Chem. 2009, 5998-6008 which is incorporated herein by reference in itsentirety). Intermediates of IV-5 upon selective hydrolysis of carbamatefollowed by appropriate amide formation give compounds of formula IV-6.Compounds of formula IV-5 may also be transformed to compounds offormula IX where Y⁵ is —NHC(O)—O— by hydrolysis.

Intermediates of formula V-3 may be prepared as shown in Scheme 5. V-3may be used in the preparation of compound of formula IX. Suchintermediates of formula V-3 can be synthesized from V-2 where X′ is atriflate or bromo or iodo group. Synthesis of boronates of V-3 may beachieved via Miyaura borylation reaction by cross-coupling ofbis(pinacolato)diboron (B₂pin₂) with aryl halides (J. Org. Chem., 1995,60, 7508-7510). The coupling of aryl halides with terminal acetylenescatalyzed by palladium and other transition metals may be achieved viaSonogashira cross-coupling reaction to give acetylenes of formula V-3(Chem. Soc. Rev., 2011, 40, 5084-5121). Compounds where X′ issubstituted with bromo or iodo groups can be attained from appropriatelyprotected commercial 2,5-hydroxy-benzoic acid derivatives (J. Med.Chem., 2003, 46, 3437-3440, which is incorporated herein by reference inits entirety). Intermediates of V-2 can also be prepared viacarboxylation of derivatives of formula V-1 where Z′ is a fluoro or OR′or SR′ by the method described in WO 2012/106995, which is incorporatedherein by reference in its entirety.

Synthesis of Prodrugs

Compounds of formula IX where the R is a prodrug moiety may besynthesized by a variety of known methods of different carboxylic acidprodrugs (Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed.,Springer, N.Y., 2007, which is incorporated herein by reference in itsentirety). These prodrugs include but are not limited to substituted ornon-substituted alkyl esters, (acyloxy)alkyl (Synthesis 2012, 44, 207,which is incorporated herein by reference in its entirety),[(alkoxycarbonyl)oxy]methyl esters (WO10097675, which is incorporatedherein by reference in its entirety), or (oxodioxolyl)methyl esters (J.Med. Chem. 1996, 39, 323-338, which is incorporated herein by referencein its entirety). Such prodrugs can be made from compounds of formulaVI-1 where R═H by treatment with acid or in neutral conditions (e.g.,carbodiimide coupling) in the presence of alcohols (ROH) or via basepromoted esterification with RX where X is a leaving group in thepresence of an appropriate base.

One exemplary but non-limiting general synthetic scheme for preparingprodrugs is shown in Scheme 6. The boronic acid of formula VI-1 where Ris hydrogen can react with a chloro/bromo-substituted prodrug moiety toform a prodrug of formula IX where R is a prodrug moiety. Examples ofthe prodrug moiety R can be —C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, and

Alternatively, boronate derivatives of formula VII-1 where Z is aboronate ester of pinacol or pinanediol or boramide of1,8-diaminonaphthalene (J. Am. Chem. Soc., 2007, 129, 758) orcorresponding tetrafluoroborates (Chem. Rev. 2008, 108, 288-325), whichis incorporated herein by reference in its entirety) may be alsoutilized for introduction of prodrugs and convert them to final prodrugsas shown in Scheme 7. Such carboxylic acids (VII-1) can be made fromcompounds of formula I-4 by selective deprotection of OR′. The prodruggroup may also be introduced earlier in the sequence in compounds offormula I-1 where R′ is R. Such sequence where prodrug is introduced inearlier intermediates is only feasible when the ester is stable underthe final deprotection conditions to remove the phenol protective groupand boronate ester group.

Administration and Pharmaceutical Compositions

The compounds are administered at a therapeutically effective dosage.While human dosage levels have yet to be optimized for the compoundsdescribed herein, generally, a daily dose may be from about 0.25 mg/kgto about 120 mg/kg or more of body weight, from about 0.5 mg/kg or lessto about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of bodyweight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus,for administration to a 70 kg person, the dosage range would be fromabout 17 mg per day to about 8000 mg per day, from about 35 mg per dayor less to about 7000 mg per day or more, from about 70 mg per day toabout 6000 mg per day, from about 100 mg per day to about 5000 mg perday, or from about 200 mg to about 3000 mg per day. The amount of activecompound administered will, of course, be dependent on the subject anddisease state being treated, the severity of the affliction, the mannerand schedule of administration and the judgment of the prescribingphysician.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated by reference in itsentirety. Accordingly, some embodiments include pharmaceuticalcompositions comprising: (a) a safe and therapeutically effective amountof a compound described herein (including enantiomers, diastereoisomers,tautomers, polymorphs, and solvates thereof), or pharmaceuticallyacceptable salts thereof; and (b) a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

In addition to the selected compound useful as described above, comeembodiments include compositions containing apharmaceutically-acceptable carrier. The term “pharmaceuticallyacceptable carrier” or “pharmaceutically acceptable excipient” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. In addition, various adjuvantssuch as are commonly used in the art may be included. Considerations forthe inclusion of various components in pharmaceutical compositions aredescribed, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's:The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press,which is incorporated herein by reference in its entirety.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to ananimal, preferably mammal subject, in a single dose, according to goodmedical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30minutes to about 2-6 hours), or administered as a continuous infusion,and may be given more than once during a course of therapy, though asingle administration is not specifically excluded. The skilled artisanwill recognize that the formulation does not specifically contemplatethe entire course of therapy and such decisions are left for thoseskilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety ofsuitable forms for a variety of routes for administration, for example,for oral, nasal, rectal, topical (including transdermal), ocular,intracerebral, intracranial, intrathecal, intra-arterial, intravenous,intramuscular, or other parental routes of administration. The skilledartisan will appreciate that oral and nasal compositions comprisecompositions that are administered by inhalation, and made usingavailable methodologies. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. Pharmaceutically-acceptablecarriers include, for example, solid or liquid fillers, diluents,hydrotropies, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid should be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J PharmSci and Tech 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual dose of the active compounds described herein depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

Methods of Treatment

Some embodiments of the present invention include methods of treatingbacterial infections with the compounds and compositions comprising thecompounds described herein. Some methods include administering acompound, composition, pharmaceutical composition described herein to asubject in need thereof. In some embodiments, a subject can be ananimal, e.g., a mammal (including a human). In some embodiments, thebacterial infection comprises a bacteria described herein. As will beappreciated from the foregoing, methods of treating a bacterialinfection include methods for preventing bacterial infection in asubject at risk thereof.

In some embodiments, the subject is a human.

Further embodiments include administering a combination of compounds toa subject in need thereof. A combination can include a compound,composition, pharmaceutical composition described herein with anadditional medicament.

Some embodiments include co-administering a compound, composition,and/or pharmaceutical composition described herein, with an additionalmedicament. By “co-administration,” it is meant that the two or moreagents may be found in the patient's bloodstream at the same time,regardless of when or how they are actually administered. In oneembodiment, the agents are administered simultaneously. In one suchembodiment, administration in combination is accomplished by combiningthe agents in a single dosage form. In another embodiment, the agentsare administered sequentially. In one embodiment the agents areadministered through the same route, such as orally. In anotherembodiment, the agents are administered through different routes, suchas one being administered orally and another being administeredintravenous (i.v.).

Examples of additional medicaments include an antibacterial agent,antifungal agent, an antiviral agent, an anti-inflammatory agent and ananti-allergic agent.

Preferred embodiments include combinations of a compound, composition orpharmaceutical composition described herein with an antibacterial agentsuch as a β-lactam. Examples of such β-lactams include Amoxicillin,Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin,Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin),Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin,Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin,Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g.,Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin,Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,Panipenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin,Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole,Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef,Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir,Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone,Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram,Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime,Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftiofur,Cefquinome, Cefovecin, Aztreonam, Tigemonam and Carumonam.

Preferred embodiments include β-lactams such as Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil,Apapenem, and Panipenem.

Additional preferred embodiments include β-lactams such as Aztreonam,Tigemonam, and Carumonam.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a monobactam. Examples ofmonobactams include aztreonam, tigemonam, nocardicin A, carumonam, andtabtoxin. In some such embodiments, the compound, composition and/orpharmaceutical composition comprises a class A, C, or D beta-lactamaseinhibitor. Some embodiments include co-administering the compound,composition or pharmaceutical composition described herein with one ormore additional agents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a class B beta lactamaseinhibitor. An example of a class B beta lactamase inhibitor includesME1071 (Yoshikazu Ishii et al, “In Vitro Potentiation of Carbapenemswith ME1071, a Novel Metallo-β-Lactamase Inhibitor, againstMetallo-β-lactamase Producing Pseudomonas aeruginosa Clinical Isolates.”Antimicrob. Agents Chemother. doi:10.1128/AAC.01397-09 (July 2010)).Some embodiments include co-administering the compound, composition orpharmaceutical composition described herein with one or more additionalagents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises one or more agents thatinclude a class A, B, C, or D beta lactamase inhibitor. Some embodimentsinclude co-administering the compound, composition or pharmaceuticalcomposition described herein with the one or more additional agents.

Indications

The compounds and compositions comprising the compounds described hereincan be used to treat bacterial infections. Bacterial infections that canbe treated with the compounds, compositions and methods described hereincan comprise a wide spectrum of bacteria. Example organisms includegram-positive bacteria, gram-negative bacteria, aerobic and anaerobicbacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina,Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus,Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia,Haemophilus, Brucella and other organisms.

More examples of bacterial infections include Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia,Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli,Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacteraerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratiamarcescens, Francisella tularensis, Morganella morganii, Proteusmirabilis, Proteus vulgaris, Providencia alcalifaciens, Providenciarettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobactercalcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,Bordetella pertussis, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilusducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamellacatarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae,Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.The following examples will further describe the present invention, andare used for the purposes of illustration only, and should not beconsidered as limiting.

EXAMPLES

General Procedures

Materials used in preparing the cyclic boronic acid ester derivativesdescribed herein may be made by known methods or are commerciallyavailable. It will be apparent to the skilled artisan that methods forpreparing precursors and functionality related to the compounds claimedherein are generally described in the literature including, for example,procedures described in U.S. Pat. No. 7,271,186 and WO2009064414, eachof which is incorporated by reference in its entirety. In thesereactions, it is also possible to make use of variants which arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry (incorporated herein by reference in their entirety) and thelike.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

The following example schemes are provided for the guidance of thereader, and represent preferred methods for making the compoundsexemplified herein. These methods are not limiting, and it will beapparent that other routes may be employed to prepare these compounds.Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thoroughlyequipped to prepare these compounds by those methods given theliterature and this disclosure. The compound numberings used in thesynthetic schemes depicted below are meant for those specific schemesonly, and should not be construed as or confused with same numberings inother sections of the application.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

Example 1 Disodium Salt of2-Hydroxy-5-methoxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 1′)

Step 1: Synthesis of 1B

A solution of bromine (14.06 mL, 274 mmol, 1 eq.) in CH₂Cl₂ (20 mL) wasadded slowly over 8 h to a suspension of 2,6-dimethoxybenzoic acid (1A)(50 g, 274 mmol) in CH₂Cl₂ (200 mL). After stirring at rt overnight, thelight orange slurry was heated and a portion of the solvent (methylbromide, hydrogen bromide and CH₂Cl₂) was removed by distillation atatmospheric pressure (total volume distilled 100 mL). Ethanol (150 mL)was added and the remaining CH₂Cl₂ was distilled off at atmosphericpressure, slowly increasing the bath temperature to 90° C. Uponcompletion of the distillation (1 h), the heterogeneous mixture wascooled to rt. After stirring 1 h at rt, the slurry was cooled to 0° C.After stirring at 0° C. for 2 h, the solids were collected byfiltration. The filtrate was recirculated to rinse the flask and stirbar. The solids were rinsed with ethanol at 0° C. (2×50 mL), air dried,then dried under high vacuum to give 1B as fine white needles (58.23 g,85.9%).

Step 2: Synthesis of 1C

A 10-mL syringe filled with trifluoroacetic anhydride (11.25 mL, 81mmol, 2 eq) and a 20-mL syringe filled with acetone (17 mL, 232 mmol,5.7 eq) were added simultaneously via syringe pump over 24 hours to aclear solution of 1B (10 g, 40 mmol) in TFA (10 mL) at 70° C. After 1hour, the starting material began to crystallize out. TFA (5 mL) wasadded, affording a clear solution. After another hour at 70° C. thesolution became slightly heterogeneous. Upon completion of the addition,HPLC showed 89:11 product to starting material. After stirring at 70° C.overnight, the ratio was 92:8. The reaction mixture was cooled to rt,diluted with ethyl acetate (15 mL), filtered over celite, and the padand flask were rinsed with ethyl acetate (2×10 mL). The clear blackfiltrate was concentrated to dryness. The solids were taken up in ethylacetate (50 mL) and CH₂C₁₂ (10 mL, to improve solubility of the product)and washed twice with a saturated solution of NaHCO₃ (50 and 30 mL). Thebrown/black solution was concentrated to dryness. The residue was takenup in ethyl acetate (10 mL) and the mixture was heated to reflux.Heptane (3×10 mL) was added and the mixture was brought to reflux (afterthe last addition of heptane, the product started crystallizing). Theheterogeneous mixture was refluxed for 15 min and was allowed to cool tort. After stirring at rt for 2 hours and 0° C. for 2 hours, the solidswere collected by filtration. The filtrate was recirculated to rinse theflask. The solids were rinsed with 3:1 heptane/ethyl acetate at 0° C.(2×10 mL), air dried, then dried under high vacuum to give 1C as a lighttan powder (8.83 g, 76%).

Step 3: Synthesis of Compound 1D

To the solution of compound 1C (8.61 g, 30 mmol, 1.0 eq) in DMF (30 mL)was added acrylic acid (3.1 mL, 45 mmol, 1.5 eq), TEA (12.5 mL, 90 mmol,3 eq), Pd(OAc)₂ (337 mg, 1.5 mmol, 0.05 eq) and tri(o-tolyl)phosphine(913 mg, 3.0 mmol, 0.1 eq). The reaction mixture was flushed withnitrogen and stirred at 100° C. for 14 hours. The reaction mixture wasconcentrated to dryness and the solid was washed with 0.2N HCl and DCMto give compound 1D (5.3 g, 64%) as off-white solid, which is pureenough. ¹H NMR (CDCl₃, 300 MHz): δ 7.70-7.64 (m, 2H), 6.63 (d, J=9.0 Hz,1H), 6.29 (d, J=16.2 Hz, 1H), 3.89 (s, 3H), 1.65 (s, 6H).

Step 4: Synthesis of Compound 1E

To the suspension of compound 1D (5.2 g, 18.7 mmol, 1.0 eq) inchloroform (200 mL) was added bromine liquid (1.1 mL, 21.5 mmol, 1.15eq) dropwise in 5 minutes at 0° C. The reaction solution was stirred at0° C. for 2 hours before it was concentrated under reduced pressure. Theobtained yellow solid is crude compound 1E (8.2 g, 99%), which was useddirectly for next step without purification.

Step 5: Synthesis of Compound 1F

To the solution of compound 1E (8.2 g, 18.7 mmol, 1.0 eq) in DMF (24 mL)was added triethylamine (5.2 mL, 37.4 mmol, 2.0 eq) dropwise in 2minutes at 0° C. The resulting reaction mixture was slowly warmed up tort and stirred for 8 hours. The reaction mixture was diluted with EtOAcand washed with 0.1N HCl and water. After dried over Na₂SO₄, the organiclayer was concentrated and chromatography (hexanes/EtOAc=3/1 to 1/1) togive compound 1F (3.2 g) as off-white solid. ¹H NMR (CDCl₃, 300 MHz): δ8.23 (d, J=9.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.69 (d, J=9.0 Hz, 1H),6.44 (d, J=8.4 Hz, 1H), 3.99 (s, 3H), 1.72 (s, 6H).

Step 6: Synthesis of Compound 1G

The mixture of compound 1F (626 mg, 2.0 mmol, 1.0 eq),bis((+)pinanediolato)diboron (1.1 g, 3.0 mmol, 1.5 eq), PdCl₂(dppf) (163mg, 0.2 mmol, 0.1 eq) and KOAc (400 mg, 4.0 mmol, 2.0 eq) in dioxane (15mL) was stirred at 60° C. for 2 hours under nitrogen atmosphere. Thereaction mixture was diluted with EtOAc and washed with 0.1N HCl andwater. After dried over Na₂SO₄, the organic layer was concentrated andpurified by column chromatography (hexanes/EtOAc=3/1 to 1/1) to givecompound 1G (605 mg, 73%) as yellow solid. ESI-MS: [M+H]+: 413

Step 7: Synthesis of Compound 1H

To the solution of compound 1G (98 mg, 0.24 mmol, 1.0 eq) and Pd(OAc)₂(2.7 mg, 0.012 mmol, 0.05 eq) in THF (3 mL) was slowly addeddiazomethane (5 mL, freshly made, about 0.2 to 0.3 M in ether) at −10°C. in 15 minutes. The solution was slowly warmed up to rt and stirredfor 2 hours before it was concentrated to dryness. The obtained residuewas and purified by column chromatography (hexanes/EtOAc=3/1 to 1/1) togive compound 1H (70 mg, 70%) as yellow oil. ESI-MS: [M+H]⁺: 427

Step 8: Synthesis of Compound 1′

The mixture of compound 1H (95 mg, 0.22 mmol, 1.0 eq) in dioxane (1.5mL) and 3N NaOH (1.5 mL) was stirred at rt for 1 hour, LCMS indicatingthe disappearance of starting material. The reaction mixture was cooledto 0° C. and TES (200 mg), TFA (5 mL) and i-BuB(OH)₂ (80 mg) was addedin sequence. The resulting yellow clear solution was stirred at rt for 2hours before it was concentrated to dryness. The residue was dissolvedin water/MeCN and purified by prep-HPLC (C18, acetonitrile and water asmobile phases, 0.1% HCOOH). The obtained solid (26 mg) was dissolved inMeCN/water and adjusted to pH=9.5 with IN NaOH (0.22 mL). Afterlyophilization, the obtained crude sodium salt of Compound 1 wasdissolved in 0.6 mL water and was added acetone (1.1 mL) dropwise. Theresulting suspension was stirred at rt for 3 hours. The mixture wasfiltered and the solid was washed with 10% water in acetone twice togive sodium salt of Compound 1 (24 mg) as a white solid. ¹H NMR (D₂O,300 MHz): δ 6.83 (d, J=8.4 Hz, 1H), 6.15 (d, J=8.4 Hz, 1H), 3.50 (s,3H), 1.60-1.48 (m, 1H), 0.60-0.46 (m, 1H), 0.06-0.10 (m, 2H). ESI-MS:[M−H₂O+H]⁺: 217

Example 2 Disodium Salt of(1aS,7bR)-2-hydroxy-5-methoxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 2′)

Step 1: Synthesis of Compound 2A

The mixture of compound 1F (940 mg, 3.0 mmol, 1.0 eq), bis((−)pinanediolato)diboron (1.4 g, 3.9 mmol, 1.3 eq), PdCl₂(dppf) (245 mg,0.3 mmol, 0.1 eq) and KOAc (600 mg, 6.0 mmol, 2.0 eq) in dioxane (15 mL)was stirred at 60° C. for 2 hours under nitrogen atmosphere. Thereaction mixture was diluted with EtOAc and washed with 0.1N HCl andwater. After dried over Na₂SO₄, the organic layer was concentrated andpurified by column chromatography (hexanes/EtOAc=3/1 to 1/1) to givecompound 2A (560 mg, 45%) as a yellow solid. ESI-MS: [M+H]+: 413

Step 2: Synthesis of Compound 2C

To the solution of Et₂Zn (11.0 mL, 1M in hexanes, 11.0 mmol, 8.0 eq) inDCM (8 mL) was added diiodomethane (1.44 mL, 16.0 mmol, 12 eq) dropwisein 3 minutes at −78° C. under nitrogen atmosphere. The resulting whitemixture was stirred at −78° C. for 10 minutes before compound 2A (560mg, 1.36 mmol, 1.0 eq) in DCM (6 mL) was added dropwise in 5 minutes.The solution was slowly warmed up to rt in 6 hours and stirred for 30hours. The reaction mixture was quenched with saturated aqueous ammoniumchloride solution was extracted with EtOAc (2×). The combined organiclayer was dried over Na₂SO₄ and then concentrated to dryness. Theresidue was briefly purified by column chromatography (hexanes/EtOAc=3/1to 1/1) to give a mixture of two isomers (2B and 2C) (510 mg, NMR/HPLCshowed 1:3 ratio of two isomers) as yellow oil. The mixture was furtherpurified by prep-HPLC (C18, acetonitrile and water as mobile phases,0.1% HCOOH) to give 3C as a white solid (154 mg). ESI-MS: [M+H]⁺: 427.

Step 3: Synthesis of Compound 2′

The mixture of compound 2C (217 mg, 0.51 mmol, 1.0 eq) in dioxane (3.0mL) and 3N NaOH (3.0 mL) was stirred at rt for 2 hours, LCMS indicatingthe disappearance of starting material. The reaction mixture was cooledto 0° C. and TES (300 mg), TFA (5 mL) and i-BuB(OH)₂ (150 mg) was addedin sequence. The resulting yellow clear solution was stirred at rt for 2hours before it was concentrated to dryness. The residue was dissolvedin water/MeCN and purified by prep-HPLC (C18, acetonitrile and water asmobile phases, 0.1% HCOOH) to give free acid of Compound 2 (74 mg) as awhite solid. The obtained solid (74 mg) was dissolved in MeCN/water andadjusted to pH=9.5 with 1N NaOH (0.58 mL). After lyophilization, theobtained crude sodium salt of Compound 2 was dissolved in 1.5 mL waterand was added acetone (4.5 mL) dropwise. The resulting suspension wasstirred at rt for 3 hours. The mixture was filtered and the solid waswashed with 10% water in acetone twice to give Compound 2′ (82 mg) as awhite solid. ¹H NMR (D₂O, 300 MHz): δ 6.85 (d, J=8.4 Hz, 1H), 6.19 (d,J=8.4 Hz, 1H), 3.53 (s, 3H), 1.62-1.55 (m, 1H), 0.64-0.55 (m, 1H),0.12-0.050 (m, 2H). ESI-MS: [M−H2O+H]⁺: 217.

Example 3 Disodium Salt of(1aR,7bS)-2-hydroxy-5-methoxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylic acid (Compound 3′)

Step 1: Synthesis of Compound 3B

To the solution of Et₂Zn (13.6 mL, 1M in hexanes, 13.6 mmol, 8.0 eq) inDCM (8 mL) was added diiodomethane (1.69 mL, 21 mmol, 12 eq) dropwise in3 minutes at −78° C. under nitrogen atmosphere. The resulting whitemixture was stirred at −78° C. for 10 minutes before compound 1G (700mg, 1.7 mmol, 1.0 eq) in DCM (8 mL) was added dropwise in 5 minutes. Thesolution was slowly warmed up to rt in 6 hours and stirred for 30 hours.The reaction mixture was quenched with saturated aqueous ammoniumchloride solution was extracted with EtOAc (2×). The combined organiclayer was dried over Na₂SO₄ and then concentrated to dryness. Theresidue was briefly purified by column chromatography (hexanes/EtOAc=3/1to 1/1) to give a mixture of two isomers of compound 3A and 3B (670 mg,NMR/HPLC showed ˜1:3 ratio of two isomers) as yellow oil. The mixturewas further purified by prep-HPLC (C18, acetonitrile and water as mobilephases, 0.1% HCOOH) to give 330 mg pure 3B as a white solid. ESI-MS:[M+H]⁺: 427. Absolute configuration of 3B was defined by Single CrystalX-ray Analysis.

Step 2: Synthesis of Compound 3′

The mixture of compound 3B (245 mg, 0.58 mmol, 1.0 eq) in dioxane (4.0mL) and 3N NaOH (4.0 mL) was stirred at rt for 2 hours, LCMS indicatingthe disappearance of starting material. The reaction mixture was cooledto 0° C. and TES (300 mg), TFA (5 mL) and i-BuB(OH)₂ (180 mg) was addedin sequence. The resulting yellow clear solution was stirred at rt for 2hours before it was concentrated to dryness. The residue was dissolvedin water/MeCN and purified by prep-HPLC (C18, acetonitrile and water asmobile phases, 0.1% HCOOH) to give free acid Compound 3 (80 mg) as awhite solid. The obtained solid (80 mg) was dissolved in MeCN/water andadjusted to pH=9.5 with IN NaOH (0.62 mL). After lyophilization, theobtained crude sodium salt of Compound 3 was dissolved in 1.5 mL waterand was added acetone (4.5 mL) dropwise. The resulting suspension wasstirred at rt for 3 hours. The mixture was filtered and the solid waswashed with 10% water in acetone twice to give Compound 3′ (84 mg) as awhite solid. ¹H NMR (D₂O, 300 MHz): δ 6.86 (d, J=8.4 Hz, 1H), 6.20 (d,J=8.1 Hz, 1H), 3.53 (s, 3H), 1.64-1.55 (m, 1H), 0.64-0.55 (m, 1H),0.13-0.05 (m, 2H). ESI-MS: [M−H₂O+H]⁺: 217.

Example 4 Disodium Salt of 5-Fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylic acid (Compound 4′)

Step 1: Synthesis of Compound 4A

Compound 4A was prepared from Boc-t-Butyl ester intermediate (previouslydisclosed in WO 2015/179308) by TFA deprotection followed byisopropylidene protection as described in step 2 of Example 1.

Step 2: Synthesis of Compound 4B

To the solution of compound 4A (16.0 g, 58 mmol, 1.0 eq) in DMF (50 mL)was added acrylic acid (6.0 mL, 87 mmol, 1.5 eq), TEA (24 mL, 175 mmol,3 eq), Pd(OAc)₂ (651 mg, 2.9 mmol, 0.05 eq) and tri(o-tolyl)phosphine(1.77 g, 5.8 mmol, 0.1 eq). The reaction mixture was flushed withnitrogen and stirred at 100° C. for 14 hours. The reaction mixture wasconcentrated to dryness and the solid was washed with 0.2N HCl and DCMto give a yellow solid. The solid was re-crystallized in EtOAc andhexanes to give compound 4B (8.2 g, 53%) as an off-white solid. ¹H NMR(CD₃OD, 400 MHz): δ 8.01 (dd, 1H), 7.78 (d, J=16.4 Hz, 1H), 7.00 (dd,1H), 6.57 (d, J=16.0 Hz, 1H), 1.80 (s, 6H).

Step 3: Synthesis of Compound 4C

To the suspension of compound 4B (8.2 g, 30.8 mmol, 1.0 eq) inchloroform (300 mL) was added bromine liquid (1.8 mL, 35.4 mmol, 1.15eq) dropwise in 5 minutes at 0° C. The reaction solution was stirred at0° C. for 2 hours before it was concentrated under reduced pressure. Theobtained yellow solid is crude compound 4C (14.7 g), which was useddirectly for next step without purification.

Step 4: Synthesis of Compound 4D

To the solution of compound 4C (14.7 g, 30.8 mmol, 1.0 eq) in DMF (35mL) was added triethylamine (8.6 mL, 61.6 mmol, 2.0 eq) dropwise in 2minutes at 0° C. The resulting reaction mixture was slowly warmed up tort and stirred for 8 hours. The reaction mixture was diluted with EtOAcand washed with 0.1N HCl and water. After dried over Na₂SO₄, the organiclayer was concentrated and chromatography (hexanes/EtOAc=3/1 to 1/1) togive compound 4D (5.5 g) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz):δ 8.20 (dd, 1H), 7.08 (d, J=8.0 Hz, 1H), 6.88 (t, J=8.2 Hz, 1H), 6.55(d, J=8.0 Hz, 1H), 1.75 (s, 6H).

Step 5: Synthesis of Compound 4E

The mixture of compound 4D (700 mg, 2.3 mmol, 1.0 eq),bis((+)pinanediolato)diboron (1.24 g, 3.5 mmol, 1.5 eq), PdCl₂(dppf)(188 mg, 0.23 mmol, 0.1 eq) and KOAc (450 mg, 4.6 mmol, 2.0 eq) indioxane (15 mL) was stirred at 60° C. for 2 hours under nitrogenatmosphere. The reaction mixture was diluted with EtOAc and washed with0.1N HCl and water. After dried over Na₂SO₄, the organic layer wasconcentrated and purified by column chromatography (hexanes/EtOAc=3/1 to1/1) to give compound 4E (240 mg, 26%) as a yellow solid. ESI-MS:[M+H]⁺: 401.

Step 6: Synthesis of Compound 4F

To the solution of compound 4E (240 mg, 0.6 mmol, 1.0 eq) and Pd(OAc)₂(6.8 mg, 0.03 mmol, 0.05 eq) in THF (3 mL) was slowly added diazomethane(6 mL, freshly made, about 0.2 to 0.3 M in ether) at −10° C. in 15minutes. The solution was slowly warmed up to rt and stirred for 2 hoursbefore it was concentrated to dryness. The obtained residue was andpurified by column chromatography (hexanes/EtOAc=3/1 to 1/1) to givecompound 4F (240 mg, 99%) as yellow oil. ESI-MS: [M+H]⁺: 415.

Step 7: Synthesis of Compound 4′

The mixture of compound 4F (140 mg, 0.34 mmol, 1.0 eq) in dioxane (1.5mL) and 3N NaOH (1.5 mL) was stirred at rt for 1 hour, LCMS indicatingthe disappearance of starting material. The reaction mixture was cooledto 0° C. and TES (250 mg), TFA (5 mL) and i-BuB(OH)₂ (100 mg) was addedin sequence. The resulting yellow clear solution was stirred at rt for 2hours before it was concentrated to dryness. The residue was dissolvedin water/MeCN and purified by prep-HPLC (C18, acetonitrile and water asmobile phases, 0.1% TFA). The obtained solid (28 mg) was dissolved inMeCN/water and adjusted to pH=9.5 with 1N NaOH (0.27 mL). Afterlyophilization, the crude sodium salt of Compound 4 was dissolved in 1.0mL water and acetone (8.0 mL) was added dropwise. The resultingsuspension was stirred at rt for 3 hours. The mixture was filtered andthe solid was washed with 10% water in acetone twice to give Compound 4′(26 mg) as an off-white solid. ¹H NMR(D₂O, 300 MHz): δ 6.87 (t, J=7.2Hz, 1H), 6.25 (d, J=8.4 Hz, 1H), 1.65-1.56 (m, 1H), 0.67-0.57 (m, 1H),0.14-0.03 (m, 2H). F NMR(D₂O, 300 MHz): δ-124.9. ESI-MS: [M−H₂O+H]⁺:205.

Example 5 Disodium Salt of1,1-Difluoro-2-hydroxy-5-methoxy-1a,7b-dihydrocyclopropa[c][1,2]benzoxaborinine-4-carboxylic acid (Compound 5′)

Step 1: Synthesis of Compound 5A

To the suspension of compound 1G (180 mg, 0.44 mmol, 1.0 eq) and sodiumiodide (52 mg, 0.35 mmol, 0.8 eq) in THF (6 mL) was slowly added TMS-CF3(0.65 mL, 4.4 mmol, 10 eq) at 65° C. in 6 hours. After another 12 hours,the reaction mixture was cooled down and concentrated to dryness. Theobtained residue was and purified by column chromatography(hexanes/EtOAc=4/1 to 1/1) to give compound 5A (40 mg, 20%) as yellowoil. ESI-MS: [M+H]⁺: 463.

Step 2: Synthesis of Compound 5′

The mixture of compound 5A (40 mg, 0.09 mmol, 1.0 eq) in dioxane (0.7mL) and 3N NaOH (0.7 mL) was stirred at rt for 2 hours, LCMS indicatingthe disappearance of starting material. The reaction mixture was cooledto 0° C. and TES (80 mg), TFA (1.5 mL) and i-BuB(OH)₂ (30 mg) were addedin sequence. The resulting yellow clear solution was stirred at rt for 2hours before it was concentrated to dryness. The residue was dissolvedin water/MeCN and purified by prep-HPLC (C18, acetonitrile and water asmobile phases, 0.1% HCOOH). The obtained solid (10 mg) was dissolved inMeCN/water and adjusted to pH=9.5 with 1N NaOH. After lyophilization,Compound 5′ as a sodium salt (11 mg) was obtained as a yellow solid. ¹HNMR(D₂O, 300 MHz): δ6.86 (d, J=8.4 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 3.55(s, 3H), 2.37 (t, J=10.8 Hz, 1H), 1.05-0.92 (m, 1H). ESI-MS: [M−H₂O+H]⁺:253.

Example 6 Disodium Salt of(7R,10R)-6-hydroxy-3-methoxy-6a,7,10,10a-tetrahydro-6H-7,10-methanodibenzo[c,e][1,2]oxaborinine-4-carboxylicacid (Compound 6′)

Step 1: Synthesis of Compound 6A

To a mixture of Pd(OAc)₂ (273 mg, 1.22 mmol, 0.1 eq) in THF (20 mL) wasadded PPh₃ (640 mg, 2.44 mmol, 0.2 eq) and K₃PO₄.3H₂O (8.1 g, 30.5 mmol,2.5 eq) in a sealed tube. The reaction mixture was stirred at rt for 30minutes under nitrogen atmosphere before compound 1C (3.5 g, 12.2 mmol,1.0 eq), norbornadiene (2.25 g, 24.4 mmol, 2.0 eq) andbis(pinacolato)diboron (4.65 g, 18.3 mmol, 1.5 eq) were added. Themixture was then stirred at 100° C. for 16 hours before it was filteredand concentrated. The residue was purified by flash chromatography onsilica (PE/EA=20:1-8:1) to give compound 6A (800 mg, 17%) as a whitesolid. ESI-MS: [M+H]⁺: 427.

Step 2: Synthesis of Compound 6′

To a mixture of compound 6A (300 mg, 0.7 mmol, 1.0 eq) in dioxane (4 mL)and concentrated HCl (2 mL) was added i-BuB(OH)₂ (144 mg, 1.4 mmol, 2.0eq). The mixture was stirred at rt for 1 hour before it was evaporatedto dryness. The residue was dissolved in H₂O/CH₃CN (4 mL/4 mL) and wasadjusted to pH=12 with 2N NaOH. The reaction was monitored by LCMS untilall dimer was transferred to monomer. The mixture was purified byprep-HPLC (C18, acetonitrile and water as mobile phases, neutralcondition) to give Compound 6′ (13 mg, 6%) as a white solid. ESI-MS:[M+H]⁺: 287. ¹H NMR (400 MHz, CD₃OD): δ 6.95 (d, J=8.0 Hz, 1H), 6.37 (d,J=8.0 Hz, 1H), 3.82-3.74 (m, 2H), 3.67 (s, 3H), 2.62 (s, 1H), 2.20 (t,J=7.2 Hz, 2H), 1.47-1.43 (m, 1H), 1.36-1.24 (m, 1H), 0.91-0.89 (m, 1H).

Example 7 Disodium Salt of(7R,10S)-6-hydroxy-3-methoxy-6a,7,8,9,10,10a-hexahydro-6H-7,10-methanodibenzo[c,e][1,2]oxaborinine-4-carboxylicacid (Compound 7′)

Step 1: Synthesis of Compound 7A

The mixture of compound 6A (300 mg, 0.7 mmol, 1.0 eq) and Pd/C (30 mg,10% on carbon) in THF (10 mL) was stirred under hydrogen atmosphere (1atm) at rt for 16 hours until LC-MS indicated the disappearance ofstarting material. The mixture was filtered and evaporated to dryness togive compound 7A (560 mg, 54%) as a white solid. ESI-MS: [M+H]+: 429.

Step 2: Synthesis of Compound 7′

To a mixture of compound 7A (300 mg, 0.7 mmol, 1.0 eq) in dioxane (4 mL)and concentrated HCl (2 mL) was added i-BuB(OH)₂ (143 mg, 1.4 mmol, 2.0eq). The mixture was stirred at rt for 1 hour before it was evaporatedto dryness. The residue was dissolved in H₂O/CH₃CN (4 mL/4 mL) and wasadjusted to pH=12 with 2N NaOH. The reaction was monitored by LCMS untilall dimer was transferred to monomer. The mixture was purified byprep-HPLC (C18, acetonitrile and water as mobile phases, neutralcondition) to give Compound 7′ (32 mg, 15%) as a white solid. ESI-MS:[M+H]⁺: 289. ¹H NMR (400 MHz, CD₃OD): δ 6.80 (d, J=8.4 Hz, 1H), 6.27(dd, J=2, 8.4 Hz, 1H), 3.71 (s, 3H), 2.71 (d, J=9.6 Hz, 1H), 2.12 (s,1H), 1.95 (s, 1H), 1.41-1.38 (m, 2H), 1.34-1.31 (m, 1H), 1.30-1.26 (m,2H), 0.76 (d, J=9.6 Hz, 1H), 0.68 (d, J=10.0 Hz, 1H).

Example 8 3-Fluoro-2-hydroxy-7-methoxy-1,2-benzoxaborinine-8-carboxylicacid (Compound 8)

Step 1: Synthesis of 8A

A heterogeneous mixture of aryl bromide 1C (20 g, 70 mmol), vinyltrifluoroborate (11.2 g, 84 mmol, 1.2 eq) and Pd(dppf)Cl₂ (204 mg, 0.4mol %) in 7/3 1-propano/water (100 mL) was degassed with argon at rt.Et₃N (14.6 mL, 104 mmol, 1.5 eq) was added and the reaction mixture washeated at 100° C. The orange heterogeneous reaction mixture turned lightamber slightly turbid upon reaching 70° C. The orange/amber reactionmixture was cooled to 50° C. Water (60 mL) and. EA (60 mL) were added.The biphasic orange reaction mixture was cooled to rt and filtered overCelite 545 (2 g). The flask and pad were rinsed with ethyl acetate (2×10mL). The filtrate was partitioned. The organic layer was washed withwater (60 mL), then concentrated to dryness. The orange solid was takenup in 3/7 1-propanol/water (80 mL) and heated at 90° C. A biphasicsolution was obtained. Propanol (6 mL) was added to get a homogeneoussolution. Upon cooling, at 60° C., a biphasic mixture was obtained.Seeds were added and the mixture was allowed to cool to 50° C.; aheterogeneous mixture was obtained. After stirring for 1 h at 50° C. Theslurry was allowed to cool to rt then stirred at 0° C. After stirring at0° C. for 2 h, the solids were collected by filtration. The filtrate wasrecirculated to rinse the flask and the cake was rinsed with cold 7/3propanol/water (2×20 mL), air dried then dried under high vacuum to give8A as a grey solid (12.30 g, 75.4% yield).

Step 2: Synthesis of 8B

To a solution of compound 8A in DCM was bubbled with O₃ at −78° C. untilthe solution turned to slightly blue. The nitrogen was bubbled in toremove the color. The colorless solution was added dimethylsulfide (3mL) and slowly warmed up to rt in 6 hours. The solvent was removed underreduced pressure and the residue was purified by column chromatographyto give compound 8B.

Step 3: Synthesis of Compound 8C

To the solution of triphenylphosphine (1.33 g, 5.06 mmol, 1.3 eq) in THF(50 mL) was added fluorotribromomethane (1.37 g, 5.06 mmol, 1.3 eq) atrt. After 5 minutes, compound 8B (920 mg, 3.9 mmol, 1.0 eq) was added.To the resulting clear solution was slowly added diethylzinc solution(5.0 mL, 1.0 M in hexanes, 5 mmol, 1.3 eq) dropwise in 10 minutes. Thereaction mixture was stirred at rt for 20 hours before it was quenchedwith methanol (10 mL). The resulting reaction mixture was diluted withEtOAc and washed with water. After dried over Na₂SO₄, the organic layerwas concentrated and purified by column chromatography(hexanes/EtOAc=3/1 to 1/1) to give compound 8C (800 mg, 62%) as slightlyyellow oil. ¹H NMR (CDCl₃, 300 MHz): δ 7.83 (t, 1H), 6.65-6.58 (m, 1H+1Hfrom isomer 1), 6.15 (d, 1H from isomer 2), 3.95 (s, 3H).

Step 4: Synthesis of Compound 8E

To the solution of compound 8C (800 mg, 2.4 mmol, 1 eq) and compound 8D(0.59 mL, 2.9 mmol, 1.2 eq) in THF (20 mL) was added n-butyllithiumsolution (1.06 mL, 2.5 M in hexane, 2.7 mmol, 1.1 eq) dropwise over 5minutes at −78° C. under nitrogen atmosphere. The resulting solution wasslowly warmed up to rt in 3 hours before it was quenched with saturatedaqueous ammonium chloride solution. The mixture was extracted with EtOAc(2×10 mL). The combined organic layer was dried over Na₂SO₄ and thenconcentrated to dryness. The residue was briefly purified by columnchromatography (dichloromethane/EtOAc=5/1 to 1/1) to give a mixture oftwo isomers of compound 8E (520 mg, 57%) as yellow solid. ESI-MS:[M+H]⁺: 379.

Step 5: Synthesis of Compound 8

The mixture of compound 8E (460 mg, 1.2 mmol, 1.0 eq) in dioxane (6.0mL) and 3N NaOH (6.0 mL) was stirred at rt for 3 hours, LCMS indicatingthe disappearance of starting material. The mixture was adjusted to pH=3with IN HCl and was added MeCN to make a clear solution. The solutionwas purified by prep-HPLC (C18, acetonitrile and water as mobile phases,0.1% HCOOH) to give Compound 8 free acid (28 mg) as off-white solid. ¹HNMR (D₂O+CD₃CN, 300 MHz): δ 7.70 (d, J=8.7 Hz, 1H), 7.57 (d, J=20.1 Hz,1H), 7.17 (d, J=9.0 Hz, 1H), 4.10 (s, 3H). 19F NMR (D₂O+CD₃CN, 300 MHz):δ −135.47 (d). ESI-MS: [M−H₂O+H]⁺: 221.

Example 9 2-Hydroxy-7-methoxy-1,2-benzoxaborinine-8-carboxylic acid(Compound 9)

Step 1: Synthesis of Compound 9A

The mixture of compound 1F (62 mg, 0.2 mmol, 1.0 eq),bis(pinacolato)diboron (76 mg, 0.3 mmol, 1.5 eq), PdCl₂(dppf) (16 mg,0.02 mmol, 0.1 eq) and KOAc (40 mg, 0.4 mmol, 2.0 eq) in dioxane (2 mL)was stirred at 65° C. for 2 hours under nitrogen atmosphere. Thereaction mixture was diluted with EtOAc and washed with 0.1N HCl andwater. After drying over Na₂SO₄, the organic layer was concentrated andpurified by column chromatography (hexanes/EtOAc=3/1 to 1/1) to givecompound 9A (29 mg, 40%) as a yellow solid. ESI-MS: [M+H]⁺: 361.

Step 2: Synthesis of Compound 9

The mixture of compound 9A (29 mg, 0.08 mmol, 1.0 eq) in dioxane (0.5mL) and 3N NaOH (0.5 mL) was stirred at rt for 2 hours, LCMS indicatingthe disappearance of starting material. The reaction mixture wasadjusted to pH=3 and was dissolved in water/MeCN. The solution waspurified by prep-HPLC (C18, acetonitrile and water as mobile phases,0.1% HCOOH) to give Compound 9 free acid (3.6 mg) as a light yellowsolid. ¹H NMR (CD₃OD, 300 MHz): δ 7.74 (d, J=11.7 Hz, 1H), 7.47 (d,J=9.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.02 (d, J=11.7 Hz, 1H), 3.90 (s,3H). ESI-MS: [M−H₂O+H]⁺: 203.

Example 102-Hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 10)

Step 1: Synthesis of 10B

A mixture of compound 10A (20 g, 116 mmol, 1.0 eq) and DMAP (4.2 g, 34mmol, 0.3 eq) in DCM (200 mL) was added Boc₂O (37.8 g, 173 mmol, 1.5 eq)and stirred at rt for 1 hour. The reaction was monitored by TLC. Themixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica (PE/EA=50:1 to 20:1) to givecompound 10B (31 g, 98%) as light yellow oil.

Step 2: Synthesis of 10C

To the solution of compound 10B (34 g, 125 mmol, 1.0 eq) in THF (350 mL)was added LDA (75 mL, 150 mmol, 1.2 eq) dropwise at −78° C. Theresulting solution was slowly warmed up to rt and stirred for 16 hours.The reaction was monitored by TLC. The mixture was concentrated underreduced pressure and the residue was purified by flash chromatography onsilica (PE/EA=50:1 to 20:1) to give compound 10C (21.8 g, 64%) as lightyellow oil.

Step 3: Synthesis of 10D

To the solution of compound 10C (21.8 g, 79.8 mmol, 1.0 eq) in DCM (110mL) was added TFA (110 mL) at rt. After 16 hours at this temperature,the mixture was concentrated under reduced pressure and the residue waspurified by flash chromatography on silica (PE/EA=50:1 to 10:1) to givecompound 10D (13.9 g, 80%) as a white solid.

Step 4: Synthesis of 10E

To the solution of compound 10D (14.7 g, 68 mmol, 1.0 eq) in TFA (95 mL)was added DMF (65 mL) at 0° C., followed by slow addition of acetone(50.6 mL) and TFAA (65 mL) at the same time. After 16 hours at 100° C.under nitrogen atmosphere, the mixture was concentrated under reducedpressure and the residue was purified by flash chromatography on silica(PE/EA=50:1 to 10:1) to give compound 10E (7.7 g, 44%) as a yellowsolid.

Step 5: Synthesis of 10F

The mixture of compound 10E (7.54 g, 29.7 mmol, 1.0 eq), accrylic acid(3.18 g, 44.2 mmol, 1.5 eq), Pd(OAc)₂ (662 mg, 2.95 mmol, 0.1 eq),P(o-toly)₃ (1.81 g, 5.9 mmol, 0.2 eq) and TEA (8.9 g, 88.4 mmol, 3.0 eq)in DMF (150 mL) was flushed with N₂ (3×) and then stirred at 100° C. for16 hours. The mixture was concentrated under reduced pressure and theresuling solid was washed with 20% EA in hexanes to give crude compound10F (4.4 g, 60%) as a brown solid which was directly used in the nextstep without further purification.

Step 6: Synthesis of 10G

To the mixture of compound 10F (4.4 g, 17.7 mmol, 1.0 eq) in CHCl₃ (200mL) was added Br₂ (3.4 g, 21.3 mmol, 1.2 eq) over 10 min at 0° C. andstirred at this temperature for 2 hour before it was concentrated todryness. The resulting crude compound 10G (7.2 g, 99%) was a brown solidwhich was directly used into the next step.

Step 7: Synthesis of 10H

To the solution of compound 10G (7.2 g, 17.7 mmol, 1.0 eq) in DMF (100mL) was added TEA (3.59 g, 35.5 mmol, 2.0 eq) dropwise at 0° C. andstirred at rt for 16 hours before it was evaporated to dryness. Theresidue was purified by flash chromatography on silica (PE/EA=100:1 to5:1) to give compound 10H (3.0 g, 60%) as a light yellow solid.

Step 8: Synthesis of 101

The mixture of compound 10H (800 mg, 2.8 mmol, 1.0 eq),bis[(+)-pinanediolato]diboron (1.5 g, 4.3 mmol, 1.5 eq), PdCl₂(dppf)(230 mg, 0.28 mmol, 0.1 eq) and KOAc (560 mg, 5.67 mmol, 2.0 eq) indioxane (15 mL) was flushed with N₂ (3×) and heated at 65° C. for 3hours. The reaction was monitored by LCMS. The reaction mixture wasfiltered and evaporated to dryness. The residue was purified by flashchromatography on silica (PE/EA=100:1 to 5:1) to give compound 10I (240mg, 22%) as light yellow oil. ESI-MS: [M+H]⁺: 383.

Step 9: Synthesis of 10J

To the mixture of compound 101 (200 mg, 0.52 mmol, 1.0 eq) and Pd(OAc)₂(5.9 mg, 0.026 mmol, 0.05 eq) in THF (5 mL) was added CH₂N₂ (freshlymade, in 15 mL Et₂O, about 6 mmol) slowly over 1 hour at −15° C. Themixture was slowly warmed up to rt and stirred for 16 hours. The mixturewas filtered and evaporated to dryness to give compound 10J (200 mg,96%) as light yellow oil. ESI-MS: [M+H]⁺: 397.

Step 10: Synthesis of 10

To the solution of compound 10J (200 mg, 0.5 mmol, 1.0 eq) in ACN (5 mL)and water (1 mL) was added 3N NaOH (1.5 mL) at rt. After 3 hours at 30°C., the resulting mixture was added TES (2 mL), TFA (6 mL) andi-BuB(OH)₂ (77 mg, 0.76 mmol, 1.5 eq) and stirred at rt for one hour.The reaction was monitored by LC-MS. The mixture was concentrated invacuo and purified by prep-HPLC (C18) to give 10 (20 mg, 19%) as whitesolid. ¹H NMR (400 MHz, CD₃OD): δ 7.62 (dd, J=1.2, 1.6 Hz, 1H), 7.38 (d,J=8.0 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 2.33-2.27 (m, 1H), 1.23-1.17 (m,1H), 0.68-0.54 (m, 2H). ESI-MS: [M+MeCN+H]⁺: 246.

Example 11 Disodium Salt of2-hydroxy-7-methoxy-spiro[3H-1,2-benzoxaborinine-4,1′-cyclopropane]-8-carboxylicacid (Compound 11′)

Step 1: Synthesis of 11A

A mixture of compound 1C (10.0 g, 34.8 mmol, 1.0 eq),bis[(+)-pinanediolato]diboron (18.7 g, 52.2 mmol, 1.5 eq), PdCl₂(dppf)(1.42 g, 1.74 mmol, 0.05 eq) and KOAc (10.2 g, 105 mmol, 3.0 eq) indioxane (80 mL) was stirred at 85° C. for 16 h under nitrogenatmosphere. The reaction was monitored by TLC. The mixture was cooleddown, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica (PE/EA=100:0 to 5:1) to givecompound 11A (8.07 g, 60%) as a slightly yellow solid. ESI-MS: [M+H]+:387.

Step 2: Synthesis of 11B

To the solution of compound 1,1-dibromocyclopropane (4.4 g, 22.1 mmol,2.1 eq) in THF (15 mL) was added n-BuLi (6.2 mL, 15.5 mmol, 1.5 eq)slowly over 30 min at −110° C. and stirred for one hour at thistemperature. Then compound 11A (4 g, 10.36 mmol, 1.0 eq) in THF (25 mL)was added to the reaction mixture over 20 min. After 2 hours at −110°C., the reaction mixture was slowly warmed up to rt and stirred for 16hours. The mixture was quenched with saturated aqueous NH₄Cl (4 mL) andwas extracted with EA (3×20 mL). The combined organic layer was driedover Na₂SO₄ before it was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica (PE/EA=100:0 to10:1) to give compound 11B (2.0 g, 45%) as a slightly yellow solid.ESI-MS: [M+H]⁺: 427.

Step 3: Synthesis of 11C

To the solution of compound 11B (1 g, 2.3 mmol, 1.0 eq) and CH₂ICl (2.07g, 11.8 mmol, 5.1 eq) in THF (50 mL) was added n-BuLi (1.8 mL, 4.6 mmol,2.0 eq) at −78° C. After 2 hours at −78° C., the reaction mixture wasslowly warmed up to rt and stirred for 16 hours. The mixture wasquenched with saturated aqueous NH₄Cl (4 mL) and was extracted with EA(3×20 mL). The combined organic layer was dried over Na₂SO₄ before itwas concentrated under reduced pressure. The residue was purified byflash chromatography on silica (PE/EA=100:0 to 10:1) to give compound11C (380 mg, 37%) as a white solid. ESI-MS: [M+H]⁺: 441.

Step 4: Synthesis of Compound 11′

To the solution of compound 11C (190 mg, 0.432 mmol, 1.0 eq) in ACN (3mL) was added 3N NaOH (3 mL) at rt. After two hours, the resultingmixture was added TES (2 mL), TFA (5 mL) and i-BuB(OH)₂ (88 mg, 0.86mmol, 2.0 eq) and stirred at rt for 30 minutes. The reaction wasmonitored by LC-MS. The mixture was concentrated in vacuo, re-dissolvedin MeCN/water and was adjusted to pH=12 with 3N NaOH. The resultingsolution was purified by prep-HPLC (C18, neutral) to give disodium saltCompound 11′ (40 mg, 37%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ6.45 (d, J=8.8 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 3.69 (s, 3H), 0.68 (t,2H), 0.56 (t, 2H), 0.45 (s, 2H). ESI-MS: [M+H]⁺: 249.

Example 12 Disodium Salt of(1aS,7bR)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylic acid (Compound 12′)

Step 1: Synthesis of 12A and 12B

To a solution of compound 4D (2.0 g, 5.0 mmol, 1.0 eq) and Pd(OAc)₂ (56mg, 0.25 mmol, 0.05 eq) in THF (30 mL) was slowly added diazomethane(200 mL, freshly made, about 0.2 M in ether, 10 eq) at −20° C. in 2hours. The solution was slowly warmed up to rt and stirred for 12 hoursbefore it was concentrated to dryness. The obtained residue was purifiedby column chromatography (hexanes/EtOAc=3/1 to 1/1) to give a mixture ofcompound 12A and 12B (1.96 g, 99%) as yellow oil. The two isomers werefurther purified by prep-HPLC (C18, acetonitrile and water as mobilephases, 0.1% HCOOH) to give 12A (650 mg, 31%) and 12B (750 mg, 36%) aswhite solid.

¹H NMR(CDCl₃, 400 MHz) for 12A: δ 7.37-7.33 (m, 1H), 6.73 (t, J=9.2 Hz,1H), 4.02 (dd, J=1.6, 1.6 Hz, 1H), 2.27-2.24 (m, 1H), 2.15-2.08 (m, 1H),2.05-2.00 (m, 1H), 1.87 (t, J=5.2 Hz, 1H), 1.76 (s, 3H), 1.74 (s, 3H),1.29-1.21 (m, 2H), 1.19 (s, 3H), 1.17-1.13 (m, 1H), 1.07 (s, 3H), 0.69(s, 3H), 0.56-0.53 (m, 1H), 0.52-0.49 (m, 1H). ESI-MS: [M+H]⁺: 415.

¹H NMR(CDCl₃, 400 MHz) for 12B: δ 7.32-7.25 (m, 1H), 6.72 (t, J=9.2 Hz,1H), 4.00 (dd, J=1.6, 1.6 Hz, 1H), 2.28-2.24 (m, 1H), 2.17-2.14 (m, 1H),1.86-1.81 (m, 2H), 1.75 (s, 8H), 1.62 (d, J=1.2 Hz, 1H), 1.21-1.19 (m,1H), 1.18 (s, 3H), 1.17 (s, 3H), 1.16-1.13 (m, 1H), 0.72 (s, 3H),0.53-0.47 (m, 2H). ESI-MS: [M+H]⁺: 415.

Step 2: Synthesis of 12′

The mixture of compound 12A (650 mg, 1.6 mmol, 1.0 eq) in dioxane (4 mL)and 3N NaOH (1.05 mL, 2 eq) was stirred at rt for 0.5 hour, LC-MSindicating the disappearance of starting material. The reaction mixturewas cooled to 0° C. and TES (1 mL), TFA (5 mL) and i-BuB(OH)₂ (320 mg,3.14 mmol, 2 eq) were added in sequence. The resulting yellow clearsolution was stirred at rt for 0.5 hours before it was concentrated todryness. The residue was dissolved in water/MeCN and purified byprep-HPLC (C18, acetonitrile and water as mobile phases, 0.1% TFA) togive Compound 12 free acid (132 mg) as a white solid afterlyophilizatio. It was dissolved in MeCN/water and adjusted to pH=9.5with 1 N NaOH (1.02 mL). After lyophilization, the crude sodium salt wasdissolved in 2.0 mL water and was slowly added acetone (50 mL). Theresulting suspension was stirred at rt for 3 hours. The mixture wasfiltered and the solid was washed with acetone twice to give disodiumsalt Compound 12′(146 mg) as an off-white solid. ¹H NMR(D₂O, 300 MHz): δ6.87 (t, J=7.2 Hz, 1H), 6.25 (d, J=8.4 Hz, 1H), 1.65-1.56 (m, 1H),0.67-0.57 (m, 1H), 0.14 (m, 2H). ¹⁹F NMR(D₂O, 300 MHz): δ −124.9.ESI-MS: [M−H₂O+H]⁺: 205.

Example 13 Disodium Salt of(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylic acid (Compound 13′)

The mixture of compound 12B (750 mg, 1.8 mmol, 1.0 eq) in dioxane (4 mL)and 3 N NaOH (1.2 mL, 2 eq) was stirred at rt for 0.5 hour, LCMSindicated the disappearance of starting material. The reaction mixturewas cooled to 0° C., TES (1 mL), TFA (5 mL) and i-BuB(OH)₂ (369 mg, 3.6mmol, 2 eq) were added in sequence. The resulting yellow clear solutionwas stirred at rt for 0.5 hour before it was concentrated to dryness.The residue was dissolved in water/MeCN and purified by prep-HPLC (C18,acetonitrile and water as mobile phases, 0.1% TFA) to give Compound 13free acid (160 mg) as a white solid after lyophilization. It wasdissolved in MeCN/water and adjusted to pH=9.5 with 1 N NaOH (1.38 mL).After lyophilization, the crude sodium salt was dissolved in 2.0 mLwater and was slowly added acetone (50 mL). The resulting suspension wasstirred at rt for 3 hours. The mixture was filtered and the solid waswashed with acetone twice to give the disodium salt Compound 13′ (145mg) as an off-white solid. ¹H NMR (D₂O, 300 MHz): δ 6.87 (t, J=7.2 Hz,1H), 6.25 (d, J=8.4 Hz, 1H), 1.65-1.56 (m, 1H), 0.67-0.57 (m, 1H), 0.14(m, 2H). ¹⁹F NMR (D₂O, 300 MHz): δ −-124.9. ESI-MS: [M−H₂O+H]⁺: 205.

Alternatively, Compound 13′ can be synthesized utilizingenantioselective cyclopropanation method as shown in the followingscheme:

Step 1: Synthesis of 13A

Intermediate 13A was prepared from 4D using method described in step 1of Example 9.

Step 2: Synthesis of 13B

To the solution of compound 13A (23.5 g, 67.5 mmol, 1.0 eq) in acetone(675 mL) and water (41 mL) was added ammonium acetate aqueous solution(304 mL, 1M in water, 4.5 eq), followed by sodium periodate (43.4 g, 203mmol, 3.0 eq) at 0° C. The resulting reaction mixture was heated up to40° C. and stirred at this temperature until NMR and LCMS showed todisappearance of 13A (normally takes 24 hours). The reaction mixture wasfiltered with celite and washed with acetone. The filtrate wasconcentrated to about 250 mL and was extracted with dichloromethane (300mL) and ethyl acetate (300 mL). The combined organic layers were driedover Na₂SO₄ before it was concentrated under reduced pressure. The crudecompound 13B (12.0 g) was obtained as yellow solid, which was useddirectly for next step without purification. ESI-MS: [M+H]^(+:) 267.

Step 3: Synthesis of 13D

To a solution of crude compound 13B (12.0 g, ˜45 mmol, 1.0 eq) indichloromethane (150 mL) was added 13C (11.0 g, 54 mmol, 1.2 eq) andMgSO₄ (12 g). The mixture was stirred at rt for 12 hours before it wasfiltered under nitrogen atmosphere. The filtrate was added more 13C (4.6g, 23 mmol, 0.5 eq). The resulting solution of 13D was used directly fornext step without further purification. ESI-MS: [M−S4+H]⁺: 267.

Step 4: Synthesis of 13E

The solution of diethylzinc (360 mL, 1.0 M solution in hexanes, 8.0 eq)was added into dichloromethane (600 mL) at −78° C., followed bydiiodomethane (44 mL, 12 eq) dropwise. The resulting white mixture wasstirred at −78° C. for 30 minutes before the solution of 13D (˜45 mmol,dichloromethane solution from previous step, pre-cooled to −78° C.) wasadded via cannula under nitrogen atmosphere. The resulting reactionmixture was stirred at −78° C. for 3 hours and slowly warmed up to rtover a period of 4 hours. The reaction was quenched with saturatedaqueous ammonium chloride (˜1 L) and extracted with dichloromethane (500mL) and ethyl acetate (500 mL). After dried over Na₂SO₄, the organiclayer was concentrated to give crude compound 13E as yellow solid, whichwas used directly for next step without purification. ESI-MS: [M−S4+H]⁺:281.

Step 5: Synthesis of 12B

To a solution of crude compound 13E (˜45 mmol, 1.0 eq) in THF (˜150 mL)was added (+)-pinanediol (23.0 g, 135 mmol, 3.0 eq) and MgSO₄ (20 g).The resulting reaction mixture was stirred at rt for 12 hours before itwas filtered and concentrated to dryness. The obtained residue waspurified by column chromatography (hexanes/EtOAc=5/1 to 3/1) to givecompound 12B (12.1 g, ˜90% purity and ˜93% de) as yellow solid. Theproduct was further purified by re-crystallization in 10% ethyl acetatein hexanes to give 6.8 g pure 12B (>99% purity and >99% de). ¹HNMR(CDCl₃, 400 MHz) for 12B: δ 7.32-7.25 (m, 1H), 6.72 (t, J=9.2 Hz,1H), 4.00 (dd, J=1.6, 1.6 Hz, 1H), 2.28-2.24 (m, 1H), 2.17-2.14 (m, 1H),1.86-1.81 (m, 2H), 1.75 (s, 8H), 1.62 (d, J=1.2 Hz, 1H), 1.21-1.19 (m,1H), 1.18 (s, 3H), 1.17 (s, 3H), 1.16-1.13 (m, 1H), 0.72 (s, 3H),0.53-0.47 (m, 2H).

Step 6: Synthesis of Compound 13′

The mixture of compound 12B (830 mg, 2 mmol, 1.0 eq) in dioxane (8 mL)and 3N NaOH (4 mL, 6 eq) was stirred at rt for 3 hours, LC-MS indicatingthe disappearance of starting material. The reaction mixture wasadjusted to pH=2 with 6 N HCl and i-BuB(OH)₂ (815 mg, 8 mmol, 4 eq) wereadded in sequence. The resulting mixture was stirred at rt for 3 hoursand then was directly purified by prep-HPLC (C18, acetonitrile and wateras mobile phases, 0.1% HCOOH) to give compound 13 free acid (310 mg) aswhite solid after lyophilization. It was dissolved in MeCN/water andadjusted to pH=9.5 with 1 N NaOH. After lyophilization, the crude sodiumsalt was dissolved in 0.5 mL water and acetone (25 mL) was slowly added.The resulting suspension was stirred at rt for 3 hours. The mixture wasfiltered and the solid was washed with acetone twice to give 13′ (146mg) as an off-white solid. ¹H NMR (D₂O, 300 MHz): δ 6.87 (t, J=7.2 Hz,1H), 6.25 (d, J=8.4 Hz, 1H), 1.65-1.56 (m, 1H), 0.67-0.57 (m, 1H), 0.14(m, 2H). ¹⁹F NMR (D₂O, 300 MHz): δ −124.9. ESI-MS: [M−H2O+H]⁺: 205.

Example 14 Disodium Salt of4,4-dihydroxyspiro[5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-2,1′-cyclopropane]-7-carboxylicacid (Compound 14′)

Step 1: Synthesis of 14A

To a solution of compound 10E (10 g, 35.46 mmol, 1.0 eq),bis[(+)-pinanediolato]diboron (15.2 g, 42.55 mmol, 1.2 eq) andPdCl₂(dppf) (2.9 g, 3.546 mmol, 0.1 eq) in dioxane (250 mL) was addedKOAc (7.0 g, 71 mmol, 2.0 eq). The mixture was stirred at 65° C. for 3 hunder nitrogen atmosphere. Then the mixture was filtered and thefiltrate was concentrated in vacuum. The residue was purified by columnchromatography on silica gel (PE/EA, 100:1˜10:1) to give compound 14A(2.9 g, 21%).

Step 2: Synthesis of 14C

A solution of compound 14B (2.8 g, 14.04 mmol, 2.0 eq) in THF (25 mL)was cooled to −110° C., then n-BuLi (4.2 mL, 10.53 mmol, 1.5 eq) wasadded in slowly and stirred at −110° C. for 30 min. Then a solution ofcompound 14A (2.5 g, 7.02 mmol, 1.0 eq) in THF (25 mL) was added in. Themixture was stirred at rt for 30 min under nitrogen atmosphere. Afterthe reaction was complete, the mixture was poured into aq. NH₄Cl, andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄, concentrated, and purified by column chromatographyon silica gel (PE/EA, 5:1˜10:1) to give compound 14C (880 mg, 35%).

Step 3: Synthesis of 14D

To a solution of compound 14C (880 mg, 2.22 mmol, 1.0 eq) in THF (15 mL)were added CH₂ICl (2.0 g, 11.11 mmol, 5.0 eq), cooled to −78° C. To thesolution n-BuLi (2.7 mL, 6.66 mmol, 3.0 eq) was added in slowly andstirred at −78° C. for 30 min. The mixture was stirred at rt for 12 hunder nitrogen atmosphere. After the reaction was complete, the mixturewas poured into aq. NH₄Cl, extracted with DCM. The organic layer waswashed with brine, dried over Na₂SO₄, concentrated, purified by columnchromatography on silica gel (PE/EA, 5:1˜10:1) to give compound 14D (110mg, 25%).

Step 4: Synthesis of Compound 14′

To a mixture of compound 14D (100 mg, 0.24 mmol, 1.0 eq) in H₂O/CH₃CN(0.5 mL/3 mL) was added 2 N NaOH (0.24 mL, 0.48 mmol, 2.0 eq). Thesolution was stirred at rt for 1 h. To the mixture was added TFA/TES (4mL/1 mL) and i-BuB(OH)₂ (48.9 mg, 0.48 mmol, 2.0 eq). The mixture wasstirred at 30° C. for 30 min. Adjusting the solution with 1 N NaOH topH˜10. The residue was purified by prep-HPLC to give compound 14′ (4 mg,15%). LC-MS: 260[M+ACN+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (d, J=7.6 Hz,1H), 6.85 (d, J=7.6 Hz, 1H), 6.41-6.24 (m, 1H), 0.85-0.76 (m, 2H),0.69-0.64 (m, 2H), 0.56-0.51 (m, 2H).

Example 15 Disodium Salt of8-fluoro-4,4-dihydroxy-spiro[5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-2,1′-cyclopropane]-7-carboxylicacid (Compound 15′)

Step 1: Synthesis of Compound 15A

A mixture of compound 4A (7.0 g, 25.44 mmol, 1.0 eq),bis[(+)-pinanaliolato]diboron (10.9 g, 30.52 mmol, 1.2 eq) andPdCl₂(dppf) (2.08 g, 2.544 mmol, 0.1 eq) and KOAc (5.0 g, 50.88 mmol,2.0 eq) in dioxane (200 mL) stirred at 65° C. for 3 h under nitrogenatmosphere. The mixture was filtered and the filtrate was concentratedin vacuum. The residue was purified by column chromatography on silicagel (PE/EA, 100:1˜10:1) to give compound 15A (3.0 g, 31%).

Step 2: Synthesis of Compound 15B

To a solution of compound 15A (3.19 g, 16.02 mmol, 2.0 eq) in THF (25mL) at −110° C. was added n-BuLi (2.5 M, 4.8 mL, 12.01 mmol, 1.5 eq) wasadded in slowly and stirred at −110° C. for 30 min. Then a solution ofcompound 14B (3.0 g, 8.01 mmol, 1.0 eq) in THF (25 mL) was added in. Themixture was stirred at rt for 30 min under nitrogen atmosphere. Afterthe reaction was complete, the mixture was poured into aq. NH₄Cl, andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄, concentrated to give compound 15B (1.0 g, 30%).

Step 3: Synthesis of Compound 15C

To a solution of compound 15B (800 mg,1.93 mmol, 1.0 eq) and CH₂ICl(1.73 g, 9.65 mmol, 5.0 eq) in THF (15 mL) at −78° C. was added n-BuLi(2.3 mL, 5.79 mmol, 3.0 eq) slowly, and stirred at −78° C. for 30 min.The mixture was stirred under nitrogen atmosphere at rt for 12 h. Themixture was poured into aq. NH₄Cl, and extracted with DCM. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated to givecompound 15C (100 mg, 12%).

Step 4: Synthesis of Compound 15′

To a mixture of compound 15C (100 mg, 0.23 mmol, 1.0 eq) in H₂O/CH₃CN(0.5 mL/3 mL) was added 2 N NaOH (0.23 mL, 0.46 mmol, 2.0 eq) andstirred at rt for 1 h. Then the mixture was added TFA/TES (4 mL/1 mL)and i-BuB(OH)₂ (46.8 mg, 0.46 mmol, 2.0 eq). The mixture was stirred at30° C. for 30 min. T the mixture was added 1 N NaOH to adjust themixture to pH ˜10, and concentrated. The residue was purified byprep-HPLC to give compound 15′ (6 mg, 11%). LC-MS: 278 [M+ACN+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 6.75 (d, J=2.4 Hz, 1H), 6.41 (d, J=1.6 Hz, 1H),0.75-0.79 (m, 2H), 0.64-0.69 (m, 2H), 0.61-0.55 (m, 2H).

Example 16 Disodium Salt of(1aR,7bS)-2,2-dihydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 16′)

Step 1: Synthesis of Compounds 16A and 16B

To a mixture of compound 10I (2.9 g, 7.59 mmol, 1.0 eq) and Pd(OAc)₂ (85mg, 0.37 mmol, 0.05 eq) in THF (50 mL) at −15° C. was added diazomethane(200 mL) dropwise. After the addition, the resulting mixture was stirredat rt overnight, and then filtered and the filtrate was concentrated.The residue was purified by prep-HPLC to give compound 16A (860 mg, 28%)and compound 16B (950 mg, 31%).

Step 2: Synthesis of Compound 16

To a solution of compound 16B (950 mg, 2.3 mmol, 1.0 eq) in ACN/H₂O (6mL/6 mL) was added 0.5N NaOH to adjust to pH 12. The mixture was stirredat rt for 1 h. To the mixture was added i-BuB(OH)₂ (480 mg, 4.6 mol, 2.0eq) and adjust to pH˜2 using 3N HCl. The mixture was purified byprep-HPLC and lyophilized to give a free acid, which was dissolved inACN/water. The solution was adjusted to pH 9 using 0.5N NaOH. To themixture was added acetone/water (50 mL/2 mL) and stirred at rt for 3 h.The solid was filtered and washed with water, and dried to give 16′ (344mg, 63%). LC-MS: 246 [M+ACN+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J=8Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.53-6.47 (m, 1H), 1.78-1.70 (m, 1H),0.86-0.78 (m, 1H), 0.41-0.36 (m, 1H), 0.34-0.28 (m, 1H).

Example 17 Disodium Salt of5-(2-fluoroethoxy)-2,2-dihydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (compound 17′)

Step 1: Synthesis of Compound 17B

To a mixture of compound 17A (8.0 g, 51.9 mmol, 1.0 eq), acetone (4.9mL, 67.47 mmol, 1.3 eq), and DMAP (316 mg, 2.595 mmol, 0.05 eq) in DME(30 mL) at 0° C. was added thionyl chloride (4.85 mL, 67.47 mmol, 1.3eq). The reaction mixture was stirred at 0° C. for 1 h and stirred at rtfor 23 h under nitrogen atmosphere. Then the mixture was quenched byaq.NaHCO₃ and extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuum. The residuewas purified by column chromatography on a silica gel (PE/EA, 30:1) togive compound 17B (7.1 g, 70%).

Step 2: Synthesis of Compound 17C

A mixture of compound 17B (3.1 g, 15.97 mmol, 1.0 eq),2-fluoro-1-iodo-ethane (2.69 g, 15.5 mmol, 1.5 eq) and K₂CO₃ (4.27 g, 31mmol, 2.0 eq) in DMF (10 mL) was stirred at rt for 12 h under nitrogenatmosphere. Then water was added and extracted with PE:EA=2:1. Theorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo to give the crude compound 17C (3.9 g, 100%).

Step 3: Synthesis of Compound 17D

To a solution of compound 17C (3.9 g, 16 mmol, 1.0 eq) in CHCl₃ (20 mL)was added bromine (0.92 mL, 17.9 mmol, 1.1 eq). The reaction was stirredat 65° C. for 0.5 h. Then the reaction was concentrated. The residue waspurified by silica gel column chromatography (PE/EA, 5:1) to givecompound 17D (4.6 g, 89%).

Step 4: Synthesis of Compound 17E

A solution of compound 17D (4.1 g, 11.6 mmol, 1.0 eq), acrylic acid(1.68 g, 23.3 mmol, 2.0 eq), Pd(OAc)₂ (285 mg, 1.16 mmol, 0.1 eq),P(O-toly)₃ (532 mg, 1.75 mmol, 0.15 eq) and triethylamine (4.87 mL, 3.49mmol, 3.0 eq) in DMF (30 mL) was stirred at 100° C. for 12 h undernitrogen atmosphere. After being cooled to rt, the mixture was filtered.The filtrate was washed with DCM/MeOH (10:1), adjust to pH 4˜5 using0.2N HCl. The mixture was filtered to collect the solid, which was driedto give compound 17E (3.1 g, 77%).

Step 5: Synthesis of Compound 17F

To a solution of compound 17E (3.0 g, 9.7 mmol, 1.0 eq) in chloroform(30 mL) was added bromine (0.54 mL, 10.6 mmol, 1.1 eq), and stirred atrt for 12 h. The reaction was concentrated to give crude compound 17F(5.0 g).

Step 6: Synthesis of Compound 17G

To a solution of compound 17F (5.0 g, 9.7 mmol, 1.0 eq) in DMF (40 mL)at 0° C. was added triethylamine (2.7 mL, 19.4 mmol, 2.0 eq). Themixture was stirred at rt for 12 h. Water was added, and the mixture wasextracted with PE:EA=1:1. The organic layer was washed with brine, driedover Na₂SO₄, concentrated in vacuum. The residue was purified by columnchromatography on silica gel (PE/EA, 30:1-7:1) to give compound 17G(2.36 g, 64%).

Step 7: Synthesis of Compound 17H

A mixture of compound 17G (2.46 g, 7.15 mmol, 1.0 eq) in dioxane (30 mL)was degassed with N₂. Then the mixture was addedbis[(+)-pinanediolato]idiboron (3.0 g, 8.58 mmol, 1.2 eq), PdCl₂(dppf)(583 mg, 0.715 mmol, 1.0 eq) and potassium acetate (2.1 g, 2.14 mmol,3.0 eq). The resulting mixture was stirred at 58° C. for 1 h, andconcentrated. The residue was purified by prep-HPLC to give compound 17H(370 mg, 12%).

Step 8: Synthesis of Compound 17I

To a solution of compound 17H (370 mg, 0.833 mmol, 1.0 eq) in dry THF (2mL) at −30° C. was added diazomethane (10 mL, 3.332 mmol, 4.0 eq) andPd(OAc)₂ (10.2 mg, 0.042 mmol, 0.05 eq). The mixture was stirred at −30°C. for 2 h, filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EA, 1:1) togive compound 17I (340 mg, 89%).

Step 9: Synthesis of Compound 17′

To a solution of compound 17I (340 mg, 0.74 mmol, 1.0 eq) in ACN/H₂O(1.5 mL/1.5 mL) was added 2 N NaOH (0.74 mL, 1.48 mmol, 2.0 eq). Themixture was stirred at rt for 3 h. To the mixture was added i-BuB(OH)₂(151 mg, 1.48 mmol, 2.0 eq) and ACN/THF (2 mL/2 mL). The solution wasadjusted to pH 2˜3 (3 N HCl), and stirred at rt for 1 h. The mixture wasconcentrated in vacuum, adjusted to pH˜10 (1 N NaOH). The mixture waspurified by prep-HPLC (neutral conditions) to give 17′ (94 mg, 47%).LC-MS: 267[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.06 (d, J=8.8 Hz, 1H), 6.35(d, J=8 Hz, 1H), 4.75-4.55 (m, 2H), 4.22-4.13 (m, 2H), 1.85-1.76 (m,1H), 0.91-0.80 (m, 1H), 0.37-0.28 (m, 2H).

Example 18 Disodium Salt of(1aS,7bR)-2,2-dihydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 18′)

To a solution of compound 16A (860 mg, 2.1 mmol, 1.0 eq) in ACN/H₂O (6mL/6 mL) was added 0.5N NaOH to adjust to pH 12. The mixture was stirredat rt for 1 h. To the mixture was added i-BuB(OH)₂ (480 mg, 4.6 mol, 2.2eq). Using 3.0N HCl the solution was adjusted pH˜2, purified byprep-HPLC and lyophilized to give a free acid. The acid was dissolved inACN/water, and 0.5 N NaOH was added to the solution to adjust to pH 9.To the mixture was added acetone/H₂O (50 mL/2 mL), and stirred at rt for3 h. The solid was collected, and dried to give compound 18′ (340 mg,69%). LC-MS: 246 [M+ACN+H]⁺. ¹H NMR (400 MHz, CD3OD) δ 7.22 (d, J=8 Hz,1H), 7.05 (d, J=7.2 Hz, 1H), 6.52-6.48 (m, 1H), 1.79-1.71 (m, 1H),0.86-0.79 (m, 1H), 0.42-0.35 (m, 1H), 0.33-0.26 (m, 1H).

Example 19 Disodium Salt of5,6-difluoro-2,2-dihydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 19′)

Step 1: Synthesis of Compound 19B

To a mixture of compound 19A (20 g, 154 mmol, 1.0 eq) in THF (200 mL)was added Boc₂O (40.2 g, 185 mmol, 1.2 eq) and DMAP (940 mg, 7.69 mmol,0.05 eq). The mixture was stirred at rt for 1 h under nitrogenatmosphere, and was concentrated in vacuum. The residue was purified bycolumn chromatography on silica gel (PE/EA, 1:0-10:1) to give compound19B (28 g, 79%).

Step 2: Synthesis of Compound 19C

To a mixture of compound 19B (8.4 g, 36.5 mmol, 1.0 eq) in THF (20 mL)was added LDA prepared from diisopropylamine (4.1 g, 40 mmol, 1.1 eq)and n-BuLi (2.5 M, 17.5 mL, 44 mmol, 1.2 eq). The mixture was stirred atrt for 3 h under nitrogen atmosphere, and quenched with aq. NH₄Cl,extracted with EA, separated and the organic layer was washed withbrine, dried over Na₂SO₄, concentrated in vacuum. The residue waspurified by column chromatography on silica gel (PE/EA, 100:0-100:1) togive compound 19C (5.3 g, 63%).

Step 3: Synthesis of Compound 19D

To a solution of compound 19C (5.3 g, 23 mmol, 1.0 eq) in DCM (20 mL)was added NBS (4.3 g, 24 mmol, 1.05 eq) and diisopropylamine (460 mg,4.6 mmol, 0.2 eq), stirred at rt for 4 h. Then the reaction wasconcentrated to give a residue, which was purified by columnchromatography on silica gel (PE) to give compound 19D (5.0 g, 71%).

Step 4: Synthesis of Compound 19E

To a solution of compound 19D (4.0 g, 12.9 mmol, 1.0 eq) in DCM (1 mL)was added TFA (2 mL) and stirred at rt for 12 h. Then the mixture wasfiltered and the filtrate was concentrated, and purified to givecompound 19E (745 mg, 23%).

Step 5: Synthesis of Compound 19F

To a solution of compound 19E (200 mg, 0.79 mmol, 1.0 eq) in DMF (2 mL)at 0° C. was added sodium hydride (133 mg, 60%, 1.98 mmol, 2.5 eq). Themixture was stirred at 0° C. for 15 min and then benzyl bromide (299 mg,1.75 mmol, 2.2 eq) was added. The mixture was stirred at rt for 3 h, andquenched with ammonium chloride solution (1 mL). The mixture wasextracted with PE:EA=1:1. The organic layer was washed with brine, driedover Na₂SO₄, concentrated in vacuum. The residue was purified byprep-TLC to give compound 19F (100 mg, 29%).

Step 6: Synthesis of Compound 19G

To a solution of compound 19F (500 mg, 1.4 mmol, 1.0 eq) in dry DMF (4mL) was added acrylic acid (0.19 mL, 2.8 mmol, 2.0 eq), Pd(OAc)₂ (34.7mg, 0.142 mmol, 0.1 eq), P(O-toly)₃(65 mg, 0.21 mmol, 0.15 eq) andtriethylamine (0.59 mL, 4.26 mmol, 3.0 eq). The mixture was stirred at100° C. for 12 h. The mixture was filtered, and extracted with EA. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrated invacuo to give compound 19G (369 mg, 75%).

Step 7: Synthesis of Compound 19H

A mixture of compound 19G (2.33 g, 5.49 mmol, 1.0 eq) in chloroform (20mL) at 0° C. was added bromine (0.31 mL, 6.04 mmol, 1.1 eq). Theresulting mixture was stirred at rt for 12 h, and concentrated to givecrude compound 19H (2.33 g, 73%).

Step 8: Synthesis of Compound 19I

To a solution of compound 19H (2.33 g, 5.49 mmol, 1.0 eq) in DMF (15 mL)at 0° C. was added triethylamine (1.11 g, 11.0 mmol, 2.0 eq). Themixture was stirred at rt for 12 h. The mixture was concentrated invacuum. The residue was purified by column chromatography on silica gel(PE/EA, 3:1) to give compound 191 (1.73 g, 94%).

Step 9: Synthesis of Compound 19J

A mixture of compound 19I (1.68 g, 3.67 mmol, 1.0 eq) in dioxane (20 mL)was added his[(+)-pinanedioiato]diboron (1.57 g, 4.4 mmol, 1.2 eq),PdCl₂(dppf) (299 mg, 0.37 mmol, 0.1 eq) and KOAc (1.08 g, 11 mmol, 3.0eq). The resulting mixture was stirred at 59° C. for 1.5 h, and thenconcentrated. The residue was purified by prep-TLC to give compound 19J(408 mg, 22%).

Step 10: Synthesis of Compound 19K

To a solution of compound 19J (408 mg, 0.731 mmol, 1.0 eq) and Pd(OAc)₂(9 mg, 0.036 mmol, 0.05 eq) in dry THF (2 mL) −40° C. was addeddiazomethane (20 mL, 2.92 mmol, 4.0 eq) and stirred at −40° C. for 2 h,and filtered. The filtrate was concentrated in vacuo to give compound19K (379 mg, 90%).

Step 11: Synthesis of Compound 19′

To a solution of compound 19K (375 mg, 0.66 mmol, 1.0 eq) in DCM (1 mL)was added tribromoborane solution in DCM (1 M, 6.6 mL, 6.6 mmol, 10 eq).The mixture was stirred at rt for 1 h. The mixture was concentrated,dissolve in acetonitrile and water (1 mL/1 mL), and purified byprep-HPLC to give a free acid (28.7 mg), which was treated with 0.1NNaOH (2.0 eq) in MeCN/H₂O at rt for 2 h. The mixture was purified byprep-HPLC again to give 19′ (28.2 mg, 18%) as a white solid. LC-MS: 282[M+MeCN+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.05-6.93 (m, 1H), 1.85-1.76 (m,1H), 0.91-0.83 (m, 1H), 0.48-0.31 (m, 2H).

Example 20 Disodium Salt of(1aS,7bR)-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[6,7]oxaborinino[2,3-c]pyridine-4-carboxylicacid (Compound 20′)

Step 1: Synthesis of Compound 20B

To a solution of compound 20A (100.0 g, 0.719 mol, 1.0 eq) in methanol(1.5 L) was added conc. sulfuric acid (120 mL, 2.157 mol, 3.0 eq) andthe reaction mixture was heated to reflux (83° C.) overnight. Thesolvent was removed in vacuo, and the residue was diluted with water(1.5 L), and adjusted to pH 8.5 with solid K₂CO₃, then extracted withDCM (3×1 L). The organic phases were dried over sodium sulfate andconcentrated under reduced pressure to give compound 20B (94 g, 85%) asa slightly blue solid. ¹H NMR (400 MHz, CDCl₃) δ 10.61 (s, 1H), 8.28(dd, J=4.1, 1.4 Hz, 1H), 7.42 (dd, J=8.5, 4.2 Hz, 1H), 7.37 (dd, J=8.5,1.5 Hz, 1H), 4.05 (s, 3H)

Step 2: Synthesis of Compound 20C

To a solution of compound 20B (114 g, 0.745 mol, 1.0 eq) in water (8 L)at 10° C. was added bromine (114.6 mL, 2.235 mol, 3.0 eq). The reactionmixture was stirred at rt overnight. The reaction mixture was extractedwith DCM (2×8 L). The organic phase was separated, and dried over sodiumsulfate, and concentrated to give crude compound 20C (186 g, 81%) as aslightly yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 7.56 (s,1H), 4.06 (s, 3H).

Step 3: Synthesis of Compound 20D

To a solution of compound 20C (186 g, 0.631 mol, 1.0 eq) and cesiumcarbonate (514.3 g, 1.578 mol, 2.5 eq) in DMF (2 L) at 0° C. was addedbenzyl bromide (89.1 mL, 0.757 mol, 1.2 eq). The reaction mixture wasstirred at rt for 2 h. The reaction mixture was filtered through a padof Celite. The filtrate was concentrated under reduced pressure to givea residue, which was purified by flash column chromatography on silica(PE/EA=20:1) to give compound 20D (199 g, 83%) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.52-7.50 (d, J=6.1 Hz, 2H), 7.43-7.37(d, J=7.2 Hz, 3H), 5.13 (s, 2H), 3.92 (s, 3H).

Step 4: Synthesis of Compound 20E

A solution of compound 20D (199 g, 0.499 mol, 1.0 eq), Pd(PPh₃)₄ (28.8g, 0.025 mol, 0.05 eq) and sodium formate (37.3 g, 0.549 mol, 1.1 eq) inDMF (2 L) under nitrogen was heated at 80° C. and stirred overnight.After being filtered through a pad of Celite, the filtrate wasconcentrated under reduced pressure. The residue was triturated withMeOH/DCM/EA/PE (1:3:3:3, 2×2L), the mother liquid was concentrated underreduced pressure, and the residue was purified by flash chromatographyon silica (PE/EA=10:1) to give compound 20E (78 g, 49%) as a slightlyyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.25-8.20 (m, 1H), 7.68-7.65 (m,1H), 7.49 (m, 2H), 7.37-7.30 (m, 2H), 7.22-7.20 (m, 3.0 Hz, 1H),5.16-4.99(m, 2H), 3.89-3.88 (m, 3.0 Hz, 3H).

Step 5: Synthesis of Compound 20F

To a solution of compound 20E (78 g, 0.243 mol, 1.0 eq) in dry DMF (800mL) was added compound acrylic acid (26.3 g, 0.364 mol, 1.5 eq),Pd(OAc)₂ (3.27 g, 14.6 mmol, 0.04 eq), P(o-toly)₃ (4.44 g, 29.2 mmol,0.08 eq) and triethylamine (152 mL, 1.09 mol, 3.0 eq). The reactionmixture under N₂ was stirred at 100° C. overnight. The reaction wasmonitored by TLC. The mixture was filtered, and concentrated underreduced pressure. The solid was washed with PE:EA:MeOH=3:3:1 (2×), andfiltered. The solid was dried to give compound 20F (60.2 g, 79%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=4.9 Hz, 1H),7.96 (d, J=4.9 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 7.40-7.37 (m, 5H), 6.77(d, J=16.1 Hz, 1H), 4.96 (s, 2H), 3.85 (s, 3H).

Step 6: Synthesis of Compound 20G

To a solution of compound 20F (60.2 g, 0.192 mol, 1.0 eq) in acetic acid(1.0 L) at 5° C. was added bromine (19.7 mL, 0.384 mol, 2.0 eq). Thereaction mixture was stirred at rt for two days. The reaction wasmonitored by LCMS. Then the solvent was removed under reduced pressureto give crude compound 20G (87 g), which was used directly for the nextstep without further purification.

Step 7: Synthesis of Compound 20H

To a solution of crude compound 20G (87 g, 0.184 mmol, 1.0 eq) in DMF(1.0 L) at 0° C. was added triethylamine (76.8 mL, 0.552 mol, 3.0 eq).The reaction mixture was stirred at rt overnight. The reaction wasmonitored by LC-MS. Then the mixture was filtered and the filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography on silica (PE/EA=30:1-15:1-7:1) to give compound20H (13.2 g, 19% over two steps) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ8.50 (d, J=4.8 Hz, 1H), 7.96 (d, J=4.8 Hz, 1H), 7.43-7.37 (m, 5H), 7.24(d, J=8.3 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 5.01 (s, 2H), 3.96 (s, 3H).

Step 8: Synthesis of Compound 20I

A mixture of bromide 20H (14.8 g, 42.6 mmol, 1.0 eq),bis(pinacolato)diboron (16.3 g, 64 mmol, 1.5 eq),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (5.2 g, 6.4mmol, 0.15 eq), potassium acetate (8.4 g, 85.0 mmol, 2.0 eq) in dioxane(150 mL) was degassed and filled with nitrogen three times, and heatedat 50° C. overnight. The reaction mixture was cooled to rt, filteredthrough a pad of Celite, washed with ethyl acetate. The filtrate wasconcentrated and purified with flash column chromatography (ethylacetate: hexane=1:2 to 2:1 and DCM: MeOH, 10:1) to give boronic ester20I (14.6 g, 87%) as brown oil.

Step 9: Synthesis of Compound 20J

A mixture of 20I (4.75 g, 12.0 mmol, 1.0 eq) and (+)-pinanediol (4.08 g,24.0 mmol, 2.0 eq) in THF (50 mL) was stirred at rt overnight. Thereaction was concentrated and purified by flash column chromatography(ethyl acetate: hexane=1:3 to 1:2) to give compound 20J (4.0 g, 75%) aslight yellow oil.

Step 10: Synthesis of Compounds 20K and 20L

To a mixture of compound 20J (4.0 g, 8.95 mmol, 1.0 eq) and palladiumacetate (60 mg, 0.268 mmol, 0.03 eq) in THF (50 mL) at −10° C.(ice-water salt bath) was added diazomethane solution (0.30 M in ether,150 mL, 45 mmol, 5.0 eq) dropwise over 30 min. The brown clear solutionwas warmed up to rt and stirred overnight. The reaction mixture wasfiltered through a pad of Celite, and washed with DCM. The filtrate wasconcentrated and purified by flash column chromatography (ethylacetate:hexane=1:3 to 1:2) to give cyclopropannulated isomeric mixture(3.37 g, 82%) as yellow oil. Part of the diastereoisomer mixture waspurified with prep-HPLC (C18, 250×21 mm, 0.1% formic acid in bothacetonitrile and water) to give isomer 20K and pure isomer 20L.

Step 11: Synthesis of Compound 20′

To a solution of 20K (150 mg, 0.28 mmol, 1.0 eq) in dichloromethane (6mL) at −78° C. was added boron tribromide (0.08 mL, 0.84 mmol, 3.0 eq).The reaction mixture was slowly warmed to rt and stirred for 1 h. Themixture was concentrated to give a solid residue, which was dissolved inacetonitrile (5 mL). To the solution at rt were added 3N HCl (1.5 mL)and isobutylboronic acid (114 mg, 1.12 mmol, 4.0 eq). After beingstirred at rt for 4 h, the reaction mixture was purified by prep-HPLC(C18, 250×21 mm, 0.1% formic acid in both acetonitrile and water) togive the free acid compound 20 (34 mg, 94%). The acid product (34 mg,0.16 mmol) in acetonitrile/water (1:2, 5 mL) was treated with 0.1 N NaOH(3.5 mL), and stirred for 4 h, and lyophilized to give sodium saltcompound 20′ (50.6 mg) as an off-white solid. LC-MS: 206 [M+1]⁺. ¹H NMR(300 MHz, D₂O) δ 7.54 (d, J=5.1 Hz, 1H), 7.17 (d, J=5.4 Hz, 1H),1.82-1.75 (m, 1H), 0.96-0.87 (m, 1H), 0.45-0.28 (m, 2H).

Example 21 Disodium Salt of(1aR,7bS)-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[6,7]oxaborinino[2,3-c]pyridine-4-carboxylicacid (Compound 21′)

To a solution of compound 20L (420 mg, 0.91 mmol, 1.0 eq) indichloromethane (20 mL) at −78° C. was added boron tribromide (0.264 mL,2.74 mmol, 3.0 eq). The reaction mixture was slowly warmed to rt andstirred for 2 h. The mixture was concentrated to give a residue, whichwas dissolved in acetonitrile (10 mL). To the solution at rt were added3N HCl (3 mL) and isobutylboronic acid (200 mg, 2.0 eq). After beingstirred at rt for 4 h, the reaction mixture was concentrated, anddissolved in acetonitrile and water, and lyophilized to obtain the crudeproduct as yellow brown solid. The crude product was purified byprep-HPLC (C18, 250×21 mm, 0.1% formic acid in both acetonitrile andwater) to give the free acid compound 21 (175 mg, 94%). The acid product(175 mg, 0.85 mmol) in acetonitrile/water (1:2, 15 mL) was treated with1 N NaOH (0.85 mL), and stirred for 2 h, and lyophilized to give a crudesodium salt as a light yellow solid. The yellow solid was dissolved inwater (2.2 mL). To the solution was added acetone (20 mL). The acetonesolution was decanted, and the solid was washed with acetone (3×). Thewater/acetone washing process was repeated to give the pure productsodium salt compound 21′ (150 mg, 78%) after drying in vacuo. LC-MS: 206[M+1]⁺. ¹H NMR (300 MHz, D2O) δ 7.46 (d, J=4.8 Hz, 1H), 7.06 (d, J=5.1Hz, 1H), 1.75-1.65 (m, 1H), 0.88-0.78 (m, 1H), 0.36-0.18 (m, 2H).

Example 22 Disodium salt of2,2-dihydroxy-1a-(hydroxymethyl)-5-methoxy-1,7b-dihydrocyclopropa[c][1,2]benzoxaborinine-4-carboxylicacid (Compound 22′)

Step 1: Synthesis of Compound 8A

A mixture of compound 1C (60.0 g, 0.210 mol, 1.0 eq), potassiumvinyltrifluoroborate (42.2 g, 0.315 mol, 1.5 eq), PdCl2(dppf) (17.0 g,0.021 mol, 0.1 eq), and triethylamine (87.7 mL, 0.629 mol, 3.0 eq) indioxane (600 mL) under nitrogen was heated to 95° C. overnight. TLCshowed no 1C left. The reaction mixture was filtered through a pad ofCelite. The filtrate was concentrated under reduced pressure to give aresidue, which was purified by flash column chromatography on silica(PE/EA/DCM=2:1:1) to give compound 8A (43 g, 87%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.65 (d, J=8.9 Hz, 1H), 6.80 (dd, J=17.6, 11.4Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 5.66 (d, J=17.7 Hz, 1H), 5.41-5.11 (m,1H), 3.96 (s, 3H), 1.71 (d, J=8.9 Hz, 6H).

Step 2: Synthesis of Compound 8B

To a solution of compound 8A (23 g, 0.098 mol, 1.0 eq) in DCM (200 mL)at −78° C. was bubbled with ozone till the color of the solution turnedinto blue. The reaction mixture was stirred for 16 h. TLC showed no 8Aleft. The reaction mixture was added PPh₃ (15 g, 0.057 mol, 0.6 eq),warm to rt., stirred for 0.5 h. the reaction was monitored by TLC. Thereaction mixture was concentrated under reduced pressure to give aresidue, which was purified by flash column chromatography on silica(PE/EA/DCM=3:1:1) to give compound 8B (15 g, 64%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.08 (d, J=9.0 Hz, 1H), 6.76 (d,J=8.6 Hz, 1H), 4.05 (s, 3H), 1.79 (s, 6H).

Step 3: Synthesis of Compound 22A

To a solution of compound 8B (15 g, 0.064 mol, 1.0 eq) in dry THF (200mL) was added 2-(triphenylphosphoranylidene)acetaldehyde (35 g, 0.115mol, 1.8 eq) under nitrogen. The reaction mixture was stirred at 100° C.overnight. The reaction mixture was concentrated under reduced pressureto give a residue, which was purified by flash column chromatography onsilica (DCM/MeOH=100:1) to give compound 22A (6.0 g, 36%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 9.73-9.61 (m, 1H), 7.83-7.72 (m, 1H),7.64-7.54 (m, 1H), 6.78-6.62 (m, 2H), 4.09-3.96 (m, 3H), 1.86-1.72 (m,6H).

Step 4: Synthesis of Compound 22B

To a solution of compound 22A (6.0 g, 0.023 mol, 1.0 eq) in dry DCM (120mL) at −78° C. under nitrogen was added bromine (1.17 mL, 0.023 mol, 1.0eq). The solution was stirred for 0.5 h. Triethylamine (3.8 mL, 0.027mol, 1.2 eq) was added. The solution was warmed to rt, and stirredovernight. The reaction mixture was concentrated under reduced pressureto give a residue, which was purified by flash column chromatography onsilica (DCM/MeOH=300:1) to give compound 22B (6.2 g, 80%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 1H), 8.76 (d, J=8.5 Hz, 1H),8.06 (s, 1H), 6.79 (d, J=9.0 Hz, 1H), 4.05 (s, 3H), 1.77 (d, J=16.3 Hz,6H).

Step 5: Synthesis of Compound 22C

To a solution of compound 22B (6.2 g, 0.018 mol, 1.0 eq) in methanol (60mL) was added NaBH₄ (0.69 g, 0.018 mol, 1.0 eq) at 0° C. under nitrogen,the reaction mixture was stirred for 0.5 h, TLC showed no 22B left. Themixture was concentrated under reduced pressure to give a residue, whichwas purified by flash column chromatography on silica (DCM/MeOH=100:1)to give compound 22C (5.7 g, 92%) as a white foam solid. ¹H NMR (400MHz, CDCl₃) δ 8.10 (d, J=7.2 Hz, 1H), 7.02 (s, 1H), 6.68 (d, J=7.1 Hz,1H), 4.42 (s, 2H), 3.98 (d, J=1.8 Hz, 3H), 1.72 (d, J=1.8 Hz, 6H).

Step 6: Synthesis of Compound 22D

To a solution of compound 22C (4.5 g, 0.013 mol, 1.0 eq) and pyridine(2.1 mL, 0.026 mol, 2.0 eq) in ACN (45 mL) at 0° C. was added TBSOTf(3.6 mL, 0.016 mol, 1.2 eq) under nitrogen. The reaction mixture waswarm to rt and stirred overnight. TLC showed no 22C left. Then thesolvent was quenched with saturated NaHCO₃ (20 mL), extracted with EA(3×100 mL). The organic phases were dried over sodium sulfate andconcentrated under reduced pressure to give a residue, which waspurified by flash column chromatography on silica (PE/EA=7:1) to givecompound 22D (5.6 g, 93%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.14 (d, J=8.8 Hz, 1H), 7.14 (s, 1H), 6.67 (d, J=9.1 Hz, 1H), 4.39 (s,2H), 3.98 (s, 3H), 1.71 (s, 6H), 0.96 (s, 9H), 0.14 (s, 6H).

Step 7: Synthesis of Compound 22E

A mixture of compound 22D (5.6 g, 0.012 mol, 1.0 eq),Bis[(+)-pinanediolato]diboron (6.6 g, 0.018 mol, 1.5 eq) and KOAc (3.6g, 0.037 mol, 3.0 eq) and PdCl₂(dppf) (1.0 g, 0.001 mol, 0.1 eq) in drydioxane (60 mL) under nitrogen. The reaction mixture was stirred at 60°C. overnight. TLC showed no 22D left. Then the mixture was filtered andthe filtrate was extracted with EA (3×150 mL). The organic phase wasdried over sodium sulfate and concentrated under reduced pressure togive a residue, which was purified by flash column chromatography onsilica (PE/EA=10:1) to give compound 22E (5.5 g, 81%) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.55 (d,J=8.8 Hz, 1H), 4.42 (s, 2H), 4.28 (d, J=7.7 Hz, 1H), 3.95 (s, 3H), 2.28(dd, J=33.7, 22.5 Hz, 2H), 2.03 (s, 1H), 1.90 (s, 2H), 1.70 (s, 6H),1.36 (s, 3H), 1.16 (d, J=10.4 Hz, 1H), 0.94 (s, 15H), 0.11 (s, 6H).

Step 8: Synthesis of Compound 22F

To a solution of compound 22E (200 mg, 0.360 mmol, 1.0 eq) and Pd(OAc)₂(4 mg, 0.018 mmol, 0.05 eq) in dry THF (3 mL) at −20° C. under nitrogenwas added CH₂N₂ (0.277 M in ether, 19.5 mL, 5.4 mmol, 15 eq). Thereaction mixture was warm to rt, stirred for 4 h. The reaction wasmonitored by LCMS. Then the mixture was filtered and the filtrate wasconcentrated under reduced pressure to give a residue, which waspurified by prep-TLC (PE/EA=3.5:1) to give compound 22F (90 mg, 43.9%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J=8.8 Hz, 1H),7.24 (s, 1H), 4.04 (t, J=10.7 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 1H), 3.59(d, J=3.7 Hz, 1H), 2.20-2.13 (m, 1H), 2.08 (t, J=7.0 Hz, 1H), 2.01 (d,J=5.9 Hz, 1H), 1.84 (s, 1H), 1.76 (s, 1H), 1.70 (s, 6H), 1.59 (s, 1H),1.27 (dd, J=10.9, 6.9 Hz, 3H), 1.16 (s, 1H), 1.14 (s, 1H), 0.89 (s,12H), 0.70 (d, J=4.3 Hz, 3H), 0.50 (d, J=10.1 Hz, 1H), 0.06 (d, J=5.8Hz, 6H).

Step 9: Synthesis of Compound 22G

To a solution of compound 22F (85 mg, 0.149 mmol, 1.0 eq) in MeOH/H₂O (2mL/0.4 mL) was added KHF₂ (76 mg, 0.974 mmol, 7 eq), stirred at 30° C.for 5 h, then stirred at rt for 1d. The reaction was monitored by LCMS.The reaction was purified by prep-HPLC (under netrual condition) to givecompound 22G (30 mg, 62.5%) as a white solid. ¹H NMR (400 MHz, cd₃od) δ7.34 (d, J=8.8 Hz, 1H), 6.69 (t, J=9.0 Hz, 1H), 3.87 (s, 3H), 3.73 (d,J=10.8 Hz, 1H), 3.38 (d, J=10.9 Hz, 1H), 1.82 (t, J=7.0 Hz, 1H), 1.72(s, 6H), 1.33 (t, J=5.0 Hz, 1H), 0.88 (dd, J=8.1, 4.3 Hz, 1H).

Step 10: Synthesis of Compound 22′

To a mixture of compound 22G (30 mg, 0.093 mmol, 1.0 eq) in ACN/H₂O (0.5mL/0.5 mL) was added 3 M NaOH (0.06 mL, 0.186 mmol, 2.0 eq), stirred for2 h. The reaction was monitored by LCMS. The reaction was purified byprep-HPLC (under netrual conditions) to give compound 22′ (9.5 mg, 39%)as a white solid. ¹H NMR (400 MHz, CD3OD) δ 6.88 (d, J=8.2 Hz, 1H), 6.23(d, J=8.2 Hz, 1H), 3.95 (d, J=10.2 Hz, 1H), 3.70 (s, 3H), 3.07 (d,J=10.2 Hz, 1H), 1.48 (dd, J=7.7, 3.9 Hz, 1H), 0.53 (d, J=8.9 Hz, 2H).

Example 23 Disodium Salt of(3aS,9bS)-4,4-dihydroxy-7-methoxy-1,3,3a,9b-tetrahydrofuro[3,4-c][1,2]benzoxaborinine-6-carboxylicacid (Compound 23′)

Step 1: Synthesis of Compound 23B

A mixture of compound 23A (15.0 g, 174.8 mmol, 10.0 eq), 1C (5.0 g, 17.5mmol, 1.0 eq), X-Phos (5.0 g, 10.49 mmol, 0.6 eq), K₃PO₄ (18.5 g, 87.4mmol, 5.0 eq) and Pd₂(dba)₃ (3.2 g, 3.50 mmol, 0.2 eq) in THF (150 mL)was heated at 75° C. for 16 h under nitrogen atmosphere. The mixture wascooled to rt, filtered and the filtrate was concentrated in vacuum. Theresidue was purified by column chromatography on a silica gel (PE/EA,5:1) to give compound 23B (1.1 g, 22%).

Step 2: Synthesis of Compound 23C

To a solution of compound 23B (440 mg, 1.5 mmol, 1.0 eq) in dry THF (15mL) at −78° C., was LiHMDS (1.8 mL, 1.8 mmol, 1.2 eq) was addeddropwise. The solution was stirred −78° C. for 30 min. To the mixturewas added compoundN-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (650 mg, 1.66mmol, 1.1 eq) in dry THF (5 mL) and stirred at −78° C. for 1.5 h. Afterthe reaction was complete, the mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄, concentrated. The residue was purified by columnchromatography on a silica gel (PE/EA, 1:1) to give compound 22C (367mg, 57%).

Step 3: Synthesis of Compound 23D

To a solution of compound 23C (400 mg, 1.06 mmol, 1.0 eq) in dioxane (20mL) was added compound bis(pinacolato)diboron (323 mg, 1.27 mmol, 1.2eq), PdCl₂(dppf) (26 mg, 0.032 mmol, 0.03 eq) and KOAc (312 mg, 3.18mmol, 3.0 eq). The mixture was stirred at 80° C. overnight. To thereaction was added water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄, concentrated. Theresidue was purified by column chromatography on silica gel (PE/EA, 1:1)to give compound 23D (310 mg, 81%).

Step 4: Synthesis of Compound 23E

To a solution of compound 23D (90 mg, 0.22 mmol, 1.0 eq) in methanol (10mL) was added Pd/C (9 mg, 10% w/w). The mixture was stirred at rt for 5h, then filtered and the filtrate was concentrated to give crudecompound 23E (90 mg).

Step 5: Synthesis of Compound 23′

To a mixture of compound 23E (90 mg, 0.22 mmol, 1.0 eq) in CH₃CN/H₂O (1mL/1 mL) was added 3.0 N NaOH to adjust the solution to pH 9˜10. Themixture was stirred at rt for 12 h, purified by prep-HPLC to givecompound 23′ (17.1 mg, 29%). LC-MS: 265 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 6.83 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.01-3.94 (m, 3H),3.73 (s, 3H), 3.61-3.52 (m, 1H), 3.41-3.28 (m, 1H), 1.55-1.42 (m, 1H).

Example 24 Disodium Salt4,4-dihydroxy-7-methoxy-1,3-dihydrofuro[3,4-c][1,2]benzoxaborinine-6-carboxylicacid (Compound 24′)

Step 1: Synthesis of Compound 24A

To a solution of compound 23D (150 mg, 0.373 mmol, 1.0 eq) in CH₃OH/H₂O(1.5 mL/0.3 mL) was added KHF2 (203 mg, 2.61 mol, 7.0 eq). The mixturewas stirred at rt for 12 h. purified by prep-HPLC to give compound 24A(25 mg, 21%).

Step 2: Synthesis of Compound 24′

To a mixture of compound 24A (47 mg, 0.14 mmol, 1.0 eq) in CH₃CN/H₂O (1mL/1 mL) was added 3.0 N NaOH to adjust the mixture to pH 10. Themixture was stirred at rt for 12 h, purified by prep-HPLC to givecompound 24′ (20 mg, 52%). LC-MS: 263[M+H]⁺. ¹H NMR (400 MHz, CD3OD): δ6.69 (d, J=8.8 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.98-4.92 (m, 2H),4.86-4.81 (m, 2H), 3.75 (s, 3H).

Example 25 General Procedures for the Preparation ofChloromethylcarbonate Prodrug Precursors

To a stirred solution of chloromethyl chloroformate (5.0 mmol) andpyridine (5.1 mmol) in anhydrous dichloromethane (30 mL) at 0° C.(ice-bath) slowly added an alcohol (5.0 mmol). The reaction was warmedto rt and monitored by TLC plate. After the starting material wascompletely consumed, the solvents were removed to give a residue, whichwas purified by silica-gel flash chromatography to afford correspondingchloride prodrug precursor.

The following prodrug precursors were synthesized using the generalprocedure described above.

¹H NMR (300 MHz, CDCl₃) δ 5.72 (s, 2H), 4.32 (q, J=9.0 Hz, 2H), 1.14 (t,J=9.0 Hz, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.72 (s, 2H), 4.74-4.62 (m, 1H), 1.98-1.92 (m,2H), 1.81-1.69 (m, 2H), 1.42-1.25 (m, 5H).

¹H NMR (300 MHz, CDCl₃) δ 5.73 (s, 2H), 5.21-4.92 (m, 1H), 4.92-4.88 (m,2H), 4.73-4.69 (m, 2H).

¹H NMR (300 MHz, CDCl₃) δ 5.76 (s, 2H), 4.69 (s, 2H), 4.26 (dd, J=15.0,and 6.0 Hz, 2H), 1.30 (t, J=9.0 Hz, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.73 (s, 2H), 4.37 (t, J=6.0 Hz, 2H), 3.64 (t,J=6.0 Hz, 2H), 3.39 (s, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.73 (s, 2H), 4.90-4.81 (m, 2H), 3.97-3.90 (m,2H), 2.04-1.98 (m, 2H), 1.80-1.74 (m, 2H).

¹H NMR (300 MHz, CDCl₃) δ 5.74 (s, 2H), 4.43 (t, J=6.0 Hz, 2H), 4.31 (t,J=6.0 Hz, 2H), 2.09 (s, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.77 (s, 2H), 4.81 (s, 2H), 3.02 (s, 3H), 2.98(s, 3H).

General Procedures for the Preparation of Chloromethylacyloxy EstersProdrug Precursors

To a well stirred solution an acid (5.0 mmol) and potassium hydroxide(5.1 mmol) tetrabutylammonium hydrogen sulfate (0.5 mmol) and potassiumbicarbonate (50 mmol) in water (2 mL) and DCM (4 mL) waschloromethanesulfonyl chloride (5.0 mmol). The mixture was monitored byTLC plate. When the starting material was completely consumed, themixture was extracted with DCM for 3 times. The combined DCM solutionwas dried over sodium sulfate. The solution was concentrated and theresidue was purified by silica gel flash chromatography with eluent of10% DCM in ethyl acetate to give the product.

The following prodrug precursors were synthesized using the generalprocedure described above.

¹H NMR (300 MHz, CDCl₃) δ 5.71 (s, 2H), 4.47-4.41 (m, 1H), 3.68-3.60 (m,2H), 2.25-2.21 (m, 2H), 2.10 (s, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.71 (s, 2H), 4.01-3.91 (m, 1H), 3.46-3.38 (m,2H), 3.38-3.25 (m, 2H), 1.95-1.71 (m, 4H).

¹H NMR (300 MHz, CDCl₃) δ 5.75 (s, 2H), 4.67 (s, 2H), 2.12 (s, 3H).

¹H NMR (300 MHz, CDCl₃) δ 5.77 (s, 2H), 4.11 (s, 2H), 3.47 (s, 3H);

General Procedures for the Preparation of Compound 13 Prodrugs

A 10 mL-flask was flame-dried under vacuum, back-filled with nitrogenand cooled to rt. The flask was charged with compound 13 (100 mg, 0.45mmol, 1 eq.), potassium carbonate (186 mg, 1.35 mmol, 3 eq.), andpotassium iodide (224 mg, 1.35 mmol, 3 eq.). The reaction flask wasplaced under vacuum and back-filled with nitrogen three times. AnhydrousDMF (2 mL, 0.25 M) followed by freshly prepared chloride (0.90 mmol, 2eq.) were added via syringe under nitrogen. The resulting mixture wasstirred at 50° C. for 12 hrs under a nitrogen balloon. The reaction wasmonitored by LCMS and HPLC. After the starting material was consumed,the mixture cooled to rt. Acetonitrile (1 mL) and water (2 mL) wereadded, and the clear solution was purified preparative-HPLC to affordthe desired product after lyophilization.

The following prodrugs were synthesized using the general proceduredescribed above.

Isopropoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 25)

LCMS: 676.0 [2M+1]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J=8.4 and 6.3Hz, 1H), 6.74 (t, J=9.0 Hz, 1H), 5.99 (d, J=5.4 Hz, 1H), 5.86 (d, J=5.7Hz, 1H), 4.98-4.92 (m, 1H), 2.28-2.21 (m, 1H), 1.37-1.30 (m, 8H),0.69-0.61 (m, 1H), 0.48-0.43 (m, 1H); ¹⁹F NMR (282 MHz, CDCl₃) δ −117.4.

Butanoyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 26)

LCMS: 340.0 [M+H₂O]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.27 (t, J=6.0 Hz, 1H),6.67 (t, J=9.0 Hz, 1H), 5.94 (d, J=3.0 Hz, 1H), 5.87 (d, J=3.0 Hz, 1H),2.41-2.36 (m, 2H), 2.30-2.17 (m, 1H), 1.73-1.61 (m, 2H), 1.30-1.25 (m,1H), 0.94 (t, J=7.5 Hz, 3H), 0.67-0.57 (m, 1H), 0.46-0.38 (m, 1H); ¹⁹F(CDCl₃, 282 MHz) δ −117.6.

Cyclopropoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 27)

LCMS: 338.0 [M+H₂O]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, J=6.0 Hz, 1H),6.53 (t, J=9.0 Hz, 1H), 5.79 (d, J=3.0 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H),2.30-2.17 (m, 1H), 1.78-1.60 (m, 1H), 1.16-1.00 (m, 2H), 1.00-0.85 (m,2H), 0.58-0.60 (m, 1H), 0.48-0.42 (m, 1H); ¹⁹F (CDCl₃, 282 MHz) δ−117.6.

Acetoxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,76-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 28)

LCMS: 317.0 [M+Na]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, J=6.0 Hz, 1H),6.53 (t, J=9.0 Hz, 1H), 5.79 (d, J=3.0 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H),2.30-2.17 (m, 1H), 2.17 (s, 3H), 1.30-1.25 (m, 1H), 0.58-0.60 (m, 1H),0.48-0.42 (m, 1H); ¹⁹NMR (CDCl₃, 282 MHz) δ −117.4.

Ethoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 29)

LCMS: 646.7 [2M−H]⁻; ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, J=6.0 Hz, 1H),6.53 (t, J=9.0 Hz, 1H), 5.79 (d, J=3.0 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H),4.08 (q, J=6.0 Hz, 1H), 2.04-1.98 (m, 1H), 1.41 (t, J=3.0 Hz, 3H),1.20-1.12 (m, 1H), 0.51-0.41 (m, 1H), 0.27-0.21 (m, 1H); ¹⁹F NMR (CDCl₃,282 MHz) δ −117.2.

Cyclohexoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 30)

LCMS: 754.7 [2M−H]⁻; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (dd, J₁=15.0 Hz,J₂=8.7 Hz, 1H), 6.72 (t, J=8.4 Hz, 1H), 5.98 (d, J=6.0 Hz, 1H), 5.87 (d,J=6.0 Hz, 1H), 4.72-4.65 (m, 1H), 2.25-2.19 (m, 2H), 1.76-1.73 (m, 2H),1.56-1.45 (m, 3H), 1.42-1.20 (m, 4H), 0.67-0.61 (m, 1H), 0.48-0.43 (m,1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −117.6.

[2-(dimethylamino)-2-oxo-ethyl](1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 31):

LCMS: 308.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J=8.4 and 6.5Hz, 1H), 6.71 (t, J=9.0 Hz, 1H), 4.39 (d, J=13.8 Hz, 1H), 4.24 (d,J=13.8 Hz, 1H), 3.10 (s, 3H), 3.01 (s, 3H), 2.21-2.15 (m, 1H), 1.37-1.30(m, 1H), 0.69-0.61 (m, 1H), 0.48-0.43 (m, 1H); ¹⁹F NMR (282 MHz, CDCl₃)δ −117.4.

Oxetan-3-yloxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 32)

LCMS: 351.0 [M−H₂O]⁻; ¹H NMR (300 MHz, CDCl₃) δ 7.36 (dd, J₁=15.0 Hz,J₂=8.7 Hz, 1H), 6.74 (t, J=8.4 Hz, 1H), 6.00 (d, J=6.0 Hz, 1H), 5.90 (d,J=6.0 Hz, 1H), 5.51-5.44 (m, 1H), 4.94-4.89 (m, 1H), 4.79-4.70(m, 1H),2.04-1.98 (m, 1H), 1.41 (t, J=3.0 Hz, 3H), 1.20-1.12 (m, 1H), 0.51-0.41(m, 1H), 0.27-0.21 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −117.6.

(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 33)

LCMS: 352.0 [M+H₂O]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (t, J=6.0 Hz, 1H),6.73 (t, J=9.0 Hz, 1H), 5.08 (s, 2H), 2.22 (s, 3H), 2.30-2.17 (m, 1H),1.41-1.31 (m, 1H), 0.67-0.58 (m, 1H), 0.46-0.38 (m, 1H); ¹⁹F NMR (CDCl₃,282 MHz) δ −117.5.

1-Ethoxycarbonyloxyethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 34)

LCMS: 356.0 [M+H₂O]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.27 (m, 1H),6.73-6.68 (m, 1H), 6.12-5.96 (m, 1H), 4.27-4.23 (m, 2H), 2.22-2.17 (m,1H), 1.36 (t, J=6.0 Hz, 3H), 1.41-1.31 (m, 1H), 0.67-0.58 (m, 1H),0.46-0.38 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −117.6, −117.8.

(2-Ethoxy-2-oxo-ethoxy)carbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 35)

LC-MS: 382.8 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (dd, J₁=6.0, J₂=3.0Hz, 1H), 6.73 (t, J=9.0 Hz, 1H), 5.59 (d, J=3.0 Hz, 1H), 5.53 (d, J=3.0Hz, 1H), 4.41 (s, 2H), 4.29-4.22 (m, 2H), 2.26-2.21 (m, 1H), 1.38-1.33(m, 1H), 1.30 (t, J=3.0 Hz, 3H), 0.68-0.63 (m, 1H), 0.49-0.45 (m, 1H);¹⁹F NMR (CDCl₃, 282 MHz) δ −117.8.

2-Methoxyethoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 36)

LCMS: 355.0 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J₁=6.0, J₂=3.0Hz, 1H), 6.73 (t, J=9.3 Hz, 1H), 5.99 (d, J=6.0 Hz, 1H), 5.89 (d, J=6.0Hz, 1H), 4.39-4.36 (m, 2H), 3.66-3.64 (m, 2H), 3.39 (s, 3H), 2.03-1.97(m, 1H), 1.40-1.33 (m, 1H), 0.66-0.60 (m, 1H), 0.47-0.43 (m, 1H); ¹⁹FNMR (CDCl₃, 282 MHz) δ −116.6.

Tetrahydropyran-4-yloxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 37)

LCMS: 759.7 [2M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J₁=15.0 Hz,J₂=8.7 Hz, 1H), 6.73 (t, J=8.4 Hz, 1H), 5.99 (d, J=6.0 Hz, 1H), 5.89 (d,J=6.0 Hz, 1H), 4.91-4.86 (m, 1H), 3.98-3.89 (m, 2H), 3.58-3.51 (m, 2H),2.25-2.19 (m, 1H), 2.03-1.97 (m, 2H), 1.83-1.71 (m, 2H), 1.40-1.33 (m,1H), 0.68-0.62 (m, 1H), 0.47-0.44 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ−117.6.

[(1aR,7bS)-5-Fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carbonyl]oxymethyl(2R)-1-acetylpyrrolidine-2-carboxylate (Compound 38)

LCMS: 392.1 [M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, J=6.0 Hz, 1H),6.53 (t, J=9.0 Hz, 1H), 5.79 (d, J=3.0 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H),4.53-4.49 (m, 1H), 3.70-3.60 (m, 1H), 3.58-3.54 (m, 1H), 2.30-2.32 (m,1H), 2.21-2.01 (m, 4H), 2,12 (s, 3H), 1.30-1.25 (m, 1H), 0.58-0.60 (m,1H), 0.48-0.42 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −119.3.

Tetrahydropyran-4-carbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 39)

LCMS: 728.0 [2M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (dd, J₁=6.0, J₂=3.0Hz, 1H), 6.73 (t, J=Hz, 1H), 5.59 (d, J=6.0 Hz, 1H), 5.53 (d, J=6.0 Hz,1H), 3.95-3.91 (m, 2H), 3.46-3.37 (m, 2H), 2.64-2.59 (m, 1H), 2.26-2.21(m, 1H), 1.72-1.60 (m, 4H), 1.38-1.33 (m, 1H), 0.67-0.58 (m, 1H),0.46-0.38 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −114.6.

2-Acetoxyethoxycarbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 40)

LCMS: 763.90[2M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.14 (t, J=6.0 Hz, 1H),6.53 (t, J=9.0 Hz, 1H), 5.79 (d, J=3.0 Hz, 1H), 5.69 (d, J=3.0 Hz, 1H),4.41 (t, J=3.9 Hz, 1H), 4.32 (t, J=3.9 Hz, 1H), 2.30-2.17 (m, 1H),1.30-1.25 (m, 1H), 0.58-0.60 (m, 1H), 0.48-0.42 (m, 1H); ¹⁹F NMR (CDCl₃,282 MHz) δ −116.9.

[2-(Dimethylamino)-2-oxo-ethoxy]carbonyloxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 41)

LCMS: 399.05 [M+H₂O]⁺; ¹H NMR (300 MHz, CDCl₃) ∂ 7.31 (dd, J₁=6.0,J₂=3.0 Hz, 1H), 6.71 (t, J=9.3 Hz, 1H), 6.03 (d, J=12.0 Hz, 1H), 5.94(d, J=12.0 Hz, 1H), 4.81 (s, 2H), 3.02 (s, 3H), 2.98 (s, 3H), 2.23-2.17(m, 1H), 1.40-1.33 (m, 1H), 0.66-0.60 (m, 1H), 0.47-0.43 (m, 1H); ¹⁹FNMR (CDCl₃, 282 MHz) δ −118.2.

(2-Acetoxyacetyl)oxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 42)

LCMS: 703.90 [2M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (t, J=6.0 Hz, 1H),6.72 (t, J=9.0 Hz, 1H), 6.01 (d, J=3.0 Hz, 1H), 5.94 (d, J=3.0 Hz, 1H),4.70 (s, 1H), 2.21 (s, 3H), 2.23-2.19 (m, 1H), 1.41-1.31 (m, 1H),0.67-0.58 (m, 1H), 0.46-0.38 (m, 1H). ¹⁹F NMR (CDCl₃, 282 MHz) δ −117.8.

(2-Methoxyacetyl)oxymethyl(1aR,7bS)-5-fluoro-2-hydroxy-1a,7b-dihydro-1H-cyclopropa[c][1,2]benzoxaborinine-4-carboxylate(Compound 43)

LCMS: 647.7 [2M+H]⁺; ¹H NMR (300 MHz, CDCl₃) δ 7.33 (t, J=6.0 Hz, 1H),6.72 (t, J=9.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H), 6.01 (d, J=3.0 Hz, 1H),4.11 (s, 3H), 3.47 (s, 2H), 2.30-2.17 (m, 1H), 1.35-1.34 (m, 2H),0.67-0.58 (m, 1H), 0.46-0.38 (m, 1H); ¹⁹F NMR (CDCl₃, 282 MHz) δ −116.9.

Example 26 Potentiation of Aztreonam

The potency and spectrum of β-lactamase inhibitors (BLIs) was determinedby assessing their aztreonam potentiation activity in a dose titrationpotentiation assay using strains of various bacteria that are resistantto aztreonam due to expression of various β-lactamases. Aztreonam is amonobactam antibiotic and is hydrolyzed by the majority ofbeta-lactamases that belong to class A or C (but not class B or D). Thepotentiation effect was observed as the ability of BLI compounds toinhibit growth in the presence of sub-inhibitory concentration ofaztreonam. MICs of test strains varied from 64 μg/mL to >128 μg/mL.Aztreonam was present in the test medium at 4 μg/mL. Compounds weretested at concentrations up to 40 μg/mL. In this assay, potency ofcompounds was reported as the minimum concentration of BLI required toinhibit growth of bacteria in the presence of 4 μg/mL of aztreonam(MPC_(@4)). Table 2 summarizes the BLI potency of aztreonam potentiation(MPC_(@4)) for various strains overexpressing class A (ESBL and KPC),and class C beta-lactamases. Aztreonam MIC for each strain is alsoshown.

TABLE 2 Table 2. Activity of BLIs to potentiate aztreonam againststrains expressing class A and class C enzymes. Aztreonam MIC(μg/mL) >128 >128 >128 64 128 >128 >128 AZT AZT AZT AZT AZT AZT 64 AZTMPC4 MPC4 MPC4 MPC4 MPC4 MPC4 AZT MPC4 CTX-M-14 CTX-M-15 SHV-5 SHV-12TEM-10 KPC-2 MPC4 CMY-6 Compound KP1005 KP1009 ec308 KP1010 ec302 KP1004ECL1002 EC1010 1 X X X X X X X X 2 X X X X X X X X 3 X X X X X X X X 4 XX X X X X X X 5 X X X X X X Y X 6 Z Z Z Z Z Z Z Z 7 Z Z Z Z Z Y Z Z 8 XX X X X X X X 9 Y Y Y X Y X Y X 10 X X X X X X X X 11 X X X X X X X X 12X X X X X X X X 13 X X X X X X X X 14 Z Y Y X Y X Y X 15 X X X X X X X X16 X X X X X X X X 17 X X X X X X X X 18 X X X X X X Y X 19 X X X X X XX X 20 Y Y Y X X X Y Y 21 X X X X X X X X 22 Y Y Y X X X X X 23 X X X XX X X X 24 Y X X X X X X X Tazobactam Y Y Y X X Z Z Y Clavulanic Acid XX X X X Z Z Z X = MPC_(@4) ≤ 5 μg/mL Y = 5 μg/mL < MPC_(@4) ≤ 20 μg/mL Z= MPC_(@4) > 20 μg/mL

Example 27 Potentiation of Tigemonam

Selected β-lactamase inhibitors were also tested for their ability topotentiate the monobactam tigemonam. The potentiation effect wasobserved as the ability of BLI compounds to inhibit growth in thepresence of sub-inhibitory concentration of tigemonam. MICs of teststrains varied from 16 μg/mL to >64 μg/mL. Tigemonam was present in thetest medium at 4 μg/mL. Compounds were tested at concentrations up to 40μg/mL. In this assay potency of compounds was reported as the minimumconcentration of BLI required to inhibit growth of bacteria in thepresence of 4 μg/mL of aztreonam (MPC_(@4)). Table 3 summarizes the BLIpotency of tigemonam potentiation (MPC_(@4)) for various strainsoverexpressing class A (ESBL) and class C beta-lactamases. Tigemonam MICfor each strain is also shown.

TABLE 3 Table 3. Activity of BLIs to potentiate tigemonam againststrains expressing class A and class C enzymes. Tigemonam MIC(μg/mL) >64 >64 >64 >64 >64 16 TIG TIG TIG TIG TIG 32 TIG MPC₄ MPC₄ MPC₄MPC₄ MPC₄ TIG MPC4 CTX-M-14 CTX-M-15 SHV-5 SHV-12 TEM-10 MPC4 CMY-6Compound KP1005 KP1009 ec308 KP1010 ec302 ECL1002 EC1010 1 X X X X X X X2 X X X X X X X 3 X X X X X X X 4 X X X X X X X 5 X X X X X X X 6 Z Z ZZ Z Y Z 7 Z Z Z Z Z Z Z 8 Y X X X Y X X 9 Z Z Z Y Z X X 10 Y X X X X X X11 Y X X X Y X X 12 X X X X X X X 13 X X X X X X X 14 Z Z Z Y Z X X 15 XX X X Y X X 16 X X X X X X X 17 Y X X X X X X 18 Y Y Y X Y X X 19 X X XX X X X 20 Z Z Z Y Z X X 21 X X X X X X X 22 Y Y Y Y Y X X 23 Y X Y X ZX X 24 Y X X X Y X X Tazobactam Y Y X X X Y X Clavulanic Acid X X X X XZ Z X = MPC_(@4) ≤ 5 μg/mL Y = 5 μg/mL < MPC_(@4) ≤ 20 μg/mL Z =MPC_(@4) > 20 μg/mL

Example 28 Potentiation of Biapenem

β-lactamase inhibitors were also tested for their ability to potentiatethe carbapenem biapenem against strains producing class A (KPC) andclass D (OXA-48) carbapenemases. The potentiation effect was observed asthe ability of BLI compounds to inhibit growth in the presence of asub-inhibitory concentration of biapenem. Biapenem MIC of test strainswere 16-32 μg/mL. Biapenem was present in the test medium at 1 μg/mL.Compounds were tested at concentrations up to 40 μg/mL. In this assaypotency of compounds was reported as the minimum concentration of BLIrequired to inhibit growth of bacteria in the presence of 1 μg/mL ofbiapenem (MPC_(@1)). Table 4 summarizes the BLI potency of biapenempotentiation (MPC_(@1)) for two strains overexpressing class A (KPC) andclass D (OXA-48) carbapenemases. Biapenem MIC for each strain is alsoshown.

TABLE 4 Table 4. Activity of BLIs to potentiate biapenem against strainsexpressing class A (KPC) or class D (OXA-48) carbapenemases. BiapenemMIC (μg/mL) 32 16 16 16 BPM MPC₁ BPM MPC₁ BPM MPC₁ BPM MPC₁ KP1004OXA-48 KP1081 KP1054 Compound KPC-2 KP1086 NDM-1 VIM-1 1 X X X X 2 X X XY 3 X X X X 4 X X X X 5 X X X Y 6 Y Z Z Z 7 X Z Y Y 8 X X X X 9 X X Z Z10 X X X X 11 X X X Y 12 X X X Z 13 X X X X 14 X X X Y 15 X X X Z 16 X XX X 17 X X X X 18 X X X Y 19 X X X X 20 X X Y Y 21 X X X X 22 X X X X 23X Y X X 24 X X Y Y Tazobactam Z Y Z Z Clavulanic Y Z Z Z Acid X =MPC_(@1) ≤ 5 μg/mL Y = 5 μg/mL < MPC_(@1) ≤ 20 μg/mL Z = MPC_(@1) > 20μg/mL

Example 29 Potentiation of Meropenem

β-lactamase inhibitors were also tested for their ability to potentiatethe carbapenem meropenem against strains of Acinetobacter baumanniiproducing class D (OXA-23 and OXA-72) carbapenemases. The potentiationeffect was observed as the ability of BLI compounds to inhibit growth inthe presence of a sub-inhibitory concentration of meropenem. MeropenemMIC of test strains were 32 to >64 μg/mL. Meropenem was present in thetest medium at 8 μg/mL. Compounds were tested at concentrations up to 20μg/mL. In this assay potency of compounds was reported as the minimumconcentration of BLI required to inhibit growth of bacteria in thepresence of 8 μg/mL of meropenem (MPC_(@8)). Table 5 summarizes the BLIpotency of meropenem potentiation (MPC_(@8)) for two strainsoverexpressing OXA-72 and OXA-23 carbapenemases. Meropenem MIC for eachstrain is also shown.

TABLE 5 Table 5. Activity of BLIs to potentiate meropenem againststrains expressing class D carbapenemases from Acinetobacter baumanniiMeropenem MIC (μg/mL) >64 32 MPM MPC₈ MPM MPC₈ Compound AB1053 OXA-72AB1054 OXA-23 1 X X 2 X X 3 X X 4 X X 5 X Y 6 Z Z 7 Z Z 8 X X 9 Y Z 10 YX 11 X X 12 X Y 13 X X 14 Z X 15 Z X 16 Y X 17 Y X 18 Z X 19 Y X 20 Z Y21 Z X 22 X X 23 Z X 24 Y Y Tazobactam ND ND Clavulanic Acid ND ND X =MPC_(@1) ≤ 5 μg/mL Y = 5 μg/mL < MPC_(@1) ≤ 20 μg/mL Z = MPC_(@1) > 20μg/mL ND = Not determined.

Example 30 Inhibitory Activity

K_(i) values of inhibition of purified class A, C and D enzymes weredetermined spectrophotometrically using nitrocefin as reportersubstrate. Purified enzymes were mixed with various concentrations ofinhibitors in reaction buffer and incubated for 10 min at roomtemperature. Nitrocefin was added and substrate cleavage profiles wererecorded at 490 nm every 10 sec for 10 min. The results of theseexperiments are presented in Table 6. These experiments confirmed thatthe described compounds are inhibitors with a broad-spectrum of activitytowards various β-lactamases.

TABLE 6 Table 6. Activity of BLIs (Ki, uM) to inhibit cleavage ofnitrocefin by purified class A, C and D enZymes Ki Ki Ki Ki Ki Ki Ki KiKi (CTX-M-14, (SHV-12, (TEM-10, (KPC-2, (P99, (Pa-AmpC, (OXA-48,(OXA-23, (VIM-1, NCF), NCF), NCF), NCF), NCF), NCF), NCF), NCF), NCF),Compd. uM uM uM uM uM uM uM uM uM 1 X ND X X X X X X X 2 X ND X X X X XX Y 3 X ND X X X X X X X 4 X ND X X X X X X Y 5 X ND X X Y Z X X Z 6 Z YY X X X X Y Y 7 X Y Y X X X X X X 8 X ND X X X X X X Y 9 ND ND X X X Y XX Z 10 X X X X X X X X X 11 X X X X X X X X Y 12 X X X X X Y X X Z 13 XX X X X X X X X 14 X ND X X X X X X Z 15 X ND X X X X X X Z 16 X ND X XX X X X X 17 X ND X X X X X X X 18 X ND X X Y Y X Y Y 19 X ND X X X X XX X 20 X ND X Y Z Z X Y Z 21 X ND X Y Y Z X X Y 22 X ND X X X X X Z X 23X ND X X X Y X X Y 24 X ND X X X X X X Z Tazobactam X X X Z Z Y Y Y ZClavulanic Acid X X X Z Z Z Z Z Z X = K_(i) ≤ 0.1 μM Y = 0.1 μM < K_(i)≤ 1 μM Z = K_(i) > 1 μM ND = not determined

K_(i) values of inhibition of purified class B enzymes NDM-1 and IMP-1were determined spectrophotometrically using imipenem as reportersubstrate. Purified enzymes were mixed with various concentrations ofinhibitors in reaction buffer and incubated for 10 min at roomtemperature. Imipenem was added and substrate cleavage profiles wererecorded at 294 nm every 30 seconds for 30 minutes at 37° C. The resultsof these experiments are presented in Table 7. These experiments furtherconfirmed that the described compounds have the ability to inhibitcarbapenemase activity of metallo-beta-lactamases.

TABLE 7 Table 7. Activity of BLIs (Ki, uM) to inhibit cleavage ofimipenem by purified class B NDM-1 and IMP-1 enzymes Compd. Ki (NDM-1,IMI), uM Ki (IMP-1, IMI), uM 1 X X 2 Y Z 3 X X 4 Y Z 5 Y Z 6 Z Z 7 X X 8ND Z 9 Z Z 10 X Y 11 X Y 12 Y Z 13 X Y 14 X Z 15 Y Z 16 X X 17 X X 18 XZ 19 Y Z 20 Z ND 21 Y ND 22 X X 23 X Z 24 Y Z Tazobactam Z Z ClavulanicAcid Z Z X = K_(i) ≤ 0.1 μM Y = 0.1 μM < K_(i) ≤ 1 μM Z = K_(i) > 1 μM

Example 31 MEXAB-OPRM Dependent Efflux of BLIs

Efflux of BLIs from Pseudomonas aeruginosa by the MexAB-OprM efflux pumpwas also evaluated. The plasmid expressing the gene encoding KPC-2 wasintroduced into two strains of P. aeruginosa, PAM1032 and PAM1154 thatoverexpressed or lacked MexAB-OprM, respectively. Due to expression ofKPC-2 both strains became resistant to biapenem. Biapenem is notaffected by efflux in P. aeruginosa and both strains had the samebiapenem MIC of 32 μg/ml. Potency of BLIs to potentiate biapenem inthese strains was determined. Potency was defined as the ability of BLIto decrease MIC of biapenem 64-fold, from 32 μg/ml to 0.5 μg/ml, orMPC₆₄. The ratio of MPC64 values for each BLI in PAM1032/KPC-2 (effluxproficient) and PAM1154/KPC-2 (efflux deficient) was determined togenerate the Efflux Index (EI) as shown in Table 8.

TABLE 8 Table 8. MexAB-OprM Dependent Efflux of BLIs from P. aeruginosaPAM1032/ PAM1154/ KPC-2 KPC-2 Biapenem Biapenem Compound MPC64 MPC64 EI1 2.5 1.25 2 2 2.5 1.25 2 3 5 2.5 2 4 2.5 2.5 1 5 20 10 2 6 ND ND ND 7ND ND ND 8 2.5 2.5 1 9 >10 1.25 >8  10 ND ND ND 11 ND ND ND 12 2.5 1.252 13 2.5 2.5 1 14 40 1.25 32  15 5 1.25 4 16 1.25 0.3 4 17 20 5 4 18 50.3 16  19 5 1.25 4 20 5 5 1 21 1.25 1.25 1 22 20 10 2 23 20 20 1 24 NDND ND ND = not determined

These experiments demonstrated that the described compounds are effectedby the MexAB-OprM efflux pump from P. aeruginosa to various degrees andthat it was possible to overcome the MexAB-OprM mediated efflux.

Example 32 Stability of Compound 13 Prodrugs in Human Serum

The rate of hydrolysis for several prodrugs of 13 was evaluated in vitroby measuring their stability in human serum and human liver microsomes.

All serum stability experiments were conducted by aliquoting 10 μL oftest compound at 500 μg/mL (10× final concentration) in 95:5water:acetonitrile v/v into 1.5 mL Eppendorf tubes. Each tube wasassigned to a specific timepoint: 0, 5, 10 or 30 minutes. The tubes werethen warmed to 37° C. in a water bath along with human serum(Bioreclamations) in a separate tube. Serum esterase activity for eachlot of serum used was established by assaying an unrelated ester prodrugas a control. To initiate the reaction, 90 μL of serum was added totubes for all timepoints using a repeating-tip pipette, thereby bringingthe final concentration of test compound to 50 μg/mL and the finalconcentration of acetonitrile to 0.5% v/v. At each timepoint, thereaction was halted and serum proteins precipitated through the additionof an equal volume of cold acetonitrile containing 25 μg/mL diclofenacas an internal standard. The mixture was vortexed then centrifuged for 5minutes at 15,000 rpm. 50 μL of supernatant was then combined with 100μL of water in an amber-glass HPLC vial containing a glass insert, and10.0 μL of this mixture was injected on HPLC.

Sample analysis for serum stability experiments was conducted using anAgilent 1100 binary pump HPLC equipped with a diode array detector setto monitor absorbance at 286 nm (8 nm bandwidth). Separation wasachieved on a Waters XBridge BEH Shield 2.1×50 mm column with 5 μmparticles and a Phenomenex Gemini guard column, using a flow rate of 400μL/min with 0.1% trifluoroacetic acid in water for mobile phase A and0.1% trifluoroacetic acid in methanol for mobile phase B. Initialconditions were 80% mobile phase A, 20% mobile phase B with a 6% perminute gradient to 80% B at 10 minutes, followed by re-equilibration atinitial conditions. The samples were analyzed together with appropriateblanks in order to ensure specificity.

Chromatograms were checked for the appearance of active drug (compound13) to ensure the test compound was converted to active. The rate ofactivation was determined by monitoring the concentration of testcompound as follows. The peak area for the analyte was divided by thepeak area for the internal standard to give an area ratio. The arearatio for each timepoint was divided by the area ratio for timepoint 0to give the percent remaining at each timepoint. The natural logarithmof the percent remaining versus time was plotted using Microsoft Exceland fitted to a linear trendline. The half-life for each test compoundwas estimated by dividing the natural logarithm of 2 by the slope of thetrendline. The percent remaining for each test compound and thecalculated half-life is presented in Table 9 below.

TABLE 9 Table 9. Rate of activation of compound 13 prodrugs in humanserum at a prodrug concentration of 50.0 μg/mL Estimated half-life % of% of % of % of (minutes) initial initial initial initial (rounded arearatio area ratio area ratio area ratio to nearest Compound at t = 0 at t= 5 at t = 10 at t = 30 integer # min min min min value) 32 100 86.877.2 38.7 21 33 100 48.4 15.4 0 4 39 100 69.3 59.4 41.1 26 42 100 29.18.1 0 3 43 100 58.6 34.5 2.9 6

Example 33 Stability of Compound 13 Prodrugs in Human Liver Microsomes(HLM)

All microsome stability experiments were conducted by diluting testcompound to 2.00 μM (2× final concentration) in 50 mM pH 7.4 potassiumphosphate buffer containing 3.3 mM MgCl₂. 50 μL, of this solution wasthen aliquoted into 1.5 mL Eppendorf tubes, two per timepoint for fourspecific timepoints: 0, 5, 10 and 30 minutes. In the meantime, a 20.0mg/mL solution of human liver microsomes (XenoTech, LLC) was diluted to1.00 mg/mL (2× final concentration). Esterase activity for each lot ofmicrosomes used was established by assaying an unrelated ester prodrugas a control. Both the Eppendorfs for each timepoint and the dilutedliver microsomes were then warmed to 37° C. in a water bath. Nocofactors (e.g. NADPH) were added to ensure that only hydrolyticreactions as opposed to reactions mediated by other cofactor-dependentenzymes (e.g. CYP450 enzymes) would take place.

To initiate the reaction, 50 μL of diluted human liver microsomes wasadded to tubes for all timepoints using a repeating-tip pipette, therebybringing the final concentration of test compound to 1.00 μM and thefinal concentration of human liver microsomes to 0.500 mg/mL. At eachtimepoint, the reaction was halted and proteins precipitated through theaddition of 200 μL of 10:45:45 water:methanol:acetonitrile v/v/vcontaining an unrelated ester prodrug at 250 ng/mL as an internalstandard. The resulting mixture was vortexed and centrifuged for 5minutes at 15,000 rpm, then 100 μL of supernatant was transferred to a96-well plate and combined with 500 μL of water preparatory to analysison LC-MS.

Sample analysis for microsome stability experiments was conducted usinga 20.0 μL injection on a LEAP PAL autosampler with Agilent 1100 binarypump HPLC coupled to an AB Sciex 3200 QTrap mass spectrometer.Separation was achieved on a Waters XBridge BEH Shield 2.1×50 mm columnwith 5 μm particles and a Phenomenex Gemini guard column, using a flowrate of 400 μL/min with 0.1% formic acid in water for mobile phase A and0.1% formic acid in acetonitrile for mobile phase B. The gradient wasadjusted as needed to give the desired resolution and run time.Detection was in positive mode; source parameters and parent-daughterion selection criteria were chosen as needed for each compound toachieve an appropriate limit of detection and signal-to-noise ratio. Thesamples were analyzed together with appropriate blanks in order toensure specificity.

The rate of hydrolysis for each prodrug was determined by monitoring theconcentration of test compound as follows. The peak area for the analytewas divided by the peak area for the internal standard to give an arearatio. The area ratio for each of the two replicates at each timepointwas divided by the area ratio for timepoint 0 to give the percentremaining at each timepoint. The natural logarithm of the percentremaining versus time for all replicates was plotted using MicrosoftExcel and fitted to a linear trendline. The half-life for each testcompound was estimated by dividing the natural logarithm of 2 by theslope of the trendline. The percent remaining for each test compound andthe calculated half-life is presented in Table 10 below.

TABLE 10 Table 10. Rate of activation of compound 13 prodrugs in 0.500mg/mL human liver microsomes at a prodrug concentration of 1.00 μMEstimated Average Average Average Average half-life % of % of % of % of(minutes) initial initial initial initial (rounded area ratio area ratioarea ratio area ratio to nearest Compound at t = 0 at t = 5 at t = 10 att = 30 integer # min min min min value) 26 100 73.4 55.9 11.9 10 27 10091.4 80.4 25.0 14 28 100 50.8 23.3 19.6 15 42 100 27.1 10.3 0.4 4 43 10064.4 44.6 0.6 4

What is claimed is:
 1. A compound having the structure of the FormulaIIIb or IVb, or pharmaceutically acceptable salts thereof:

wherein each J, L, M is independently CR¹² or N, each of R² and R³ isindependently selected from the group consisting of H, amino, halogen,cyano, hydroxy, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted C₁₋₆ haloalkoxy, optionally substituted (C₁₋₆alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀ aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3- 10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl) C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR^(C),—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(=NR^(e)), —NR^(f)C(=NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d), or R² and R³ togetherwith the atoms to which they are attached form a fused ring or ringsystem selected from the group consisting of C₃₋₇carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, eachoptionally substituted with one or more R⁵; R⁵ is —Y⁵—(CH₂)_(t)-G; t isan integer of 0 or 1 ; G is selected from the group consisting of H,amino, halogen, cyano, hydroxy, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionally substituted(C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl,optionally substituted 3-10 membered heterocyclyl, optionallysubstituted C₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl,optionally substituted (C₃₋₇carbocyclyl)C₁₋₆alkyl, optionallysubstituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀ aryl)C₁₋₆alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆ alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido,—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(=NR^(e)), —NR^(f)C(=NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), and —NR^(f)S(O)₂NR^(f)OR^(d); R⁶ —C(O)OR or acarboxylic acid isostere; R is selected from the group consisting of H,C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₃₋₇ carbocyclyl,—CR¹⁰R¹¹OC(O)(3 to 7 membered heterocyclyl),—CR¹⁰R¹¹OC(O)C₂₋₈alkoxyalkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl,—CR¹⁰R¹¹OC(O)OC₃₋₇ carbocyclyl, —CR¹⁰R¹¹OC(O)O(3 to 7 memberedheterocyclyl), —CR¹⁰R¹¹OC(O)OC₂₋₈ alkoxyalkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹C(O)NR¹³R¹⁴,—CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)NR¹³R¹⁴, —CR¹⁰R¹¹OC(O)O(CH₂)₂₋₃OC(O)C₁₋₄alkyl, —CR¹⁰R¹¹OC(O)O(CH₂)₁₋₃C(O)OC₁₋₄ alkyl,

—CR¹⁰R¹¹OC(O)(CH₂)₁₋₃ OC(O)C₁₋₄ alkyl, and R⁷ is OH or optionallysubstituted C₁₋₆ alkoxy, each R¹⁰and R¹¹ is independently selected fromthe group consisting of H, optionally substituted C₁₋₄alkyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 3-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R¹² is selected from the groupconsisting of hydrogen, amino, halogen, cyano, hydroxy, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ haloalkyl,optionally substituted C₁₋₆ alkoxy, optionally substituted C₁₋₆haloalkoxy, optionally substituted C₁₋₆ alkylthiol, optionallysubstituted (C₁₋₆ alkoxy)C₁₋₆ alkyl, optionally substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substitutedC₃₋₇ carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted (C₃₋₇ carbocyclyl)C₁₋₆alkyl,optionally substituted (3-10 membered heterocyclyl)C₁₋₆alkyl, optionallysubstituted (C₆₋₁₀aryl)C₁₋₆alkyl, (C₆₋₁₀aryl)C1-6alkoxy, optionallysubstituted (5-10 membered heteroaryl)C₁₋₆alkyl, acyl, C-carboxy,O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfhydryl,—C(O)(CH₂)₀₋₃SR^(c), —C(O)(CH₂)₁₋₃R^(d), —NR^(f)C(O)NR^(f)R^(g),—NR^(f)S(O)₂NR^(f)R^(g), —C(═NR^(e))R^(c), —C(═NR^(e))NR^(f)R^(g),—NR^(f)CR^(c)(=NR^(e)), —NR^(f)C(=NR^(e))NR^(f)R^(g),—S(O)(CH₂)₁₋₃R^(c), —NR^(f)S(O)₂NR^(f)OR^(d), and—(CH₂)_(p)—Y⁶—(CH₂)_(q)K; each R¹³ and R¹⁴ is independently selectedfrom the group consisting of H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R¹⁵ is optionally substituted C₁₋₆alkyl; Y² is —O- or -S-; Y³ is —OH or —SH; Y⁴ is —OH or optionallysubstituted C₁₋₆ alkoxy; Y⁵ is selected from the group consisting of—S—, —S(O)—, —S(O)₂-, —O—, —CR^(f)R^(g)—, and —NR^(g)—, or Y⁵ is absent;Y⁶ is selected from the group consisting of —S—, —S(O)—, —S(O)₂-, —O—,—CR^(f)R^(g)—, and —NR^(f)-, K is selected from the group consisting ofC-amido; N-amido; S-sulfonamido; N-sulfonamido; —NR^(f)C(O)NR^(f)R^(g);—NR^(f)S(O)₂NR^(f)R^(g); —C(═NR^(e))R^(c); —C(═NR^(e))NR^(f)R^(g);—NR^(f)CR^(c)(=NR^(e)); —NR^(f)C(=NR^(e))NR^(f)R^(g); C₁₋₄ alkyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkoxy, amino, halogen, C-amido, and N-amido; C₆₋₁₀aryl optionally substituted with 0-2 substituents selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido,and N-amido; C₃₋₇ carbocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido; 5-10 membered heteroaryloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, halogen, C-amido, andN-amido; and 3-10 membered heterocyclyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, amino, halogen, C-amido, and N-amido; each R^(c), R^(d), R^(e),R^(f), and R^(g) are independently selected from the group consisting ofH, halogen, optionally substituted C₁₋₄alkyl, optionally substitutedC₃₋₇ carbocyclyl, optionally substituted 3-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl; and each p and q is independently 0 or
 1. 2. Thecompound of claim 1, wherein R is selected from H, C₁₋₉ alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and


3. The compound of claim 1, wherein each J, L and M is cR¹².
 4. Thecompound of claim 1, wherein R² is hydrogen, halogen, or C₁₋₆ alkyl. 5.The compound of claim 1, wherein R³ is hydrogen.
 6. The compound ofclaim 1, wherein R is H.
 7. The compound of claim 1, wherein R⁷ is —OH.8. The compound of claim 1, wherein Y² is —O—, and each of Y³ and Y⁴ is—OH.
 9. The compound of claim 3, wherein each R¹² is independentlyhydrogen, halogen or C₁₋₆ alkoxy.
 10. The compound of claim 1, selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 11. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.12. The pharmaceutical composition of claim 1, further comprising aβ-lactam antibacterial agent.
 13. A method of treating a bacterialinfection, comprising administering a compound of claim 1, or apharmaceutically acceptable salt thereof to a subject in need thereof.14. The method of claim 13, wherein the bacterial infection is caused byβ-lactam antibacterial agent-resistant enterobacteriaceae.
 15. Themethod of claim 13, further comprising administering a β-lactamantibacterial agent to the subject.
 16. The method of claim 15, whereinthe β-lactam antibacterial agent is administered separately from thecompound or pharmaceutically acceptable salt thereof, or the β-lactamantibacterial agent and the compound or pharmaceutically acceptable saltthereof are in a single dosage form.
 17. The method of claim 16, whereinthe bacterial infection is caused by Carbapenem-resistantenterobacteriaceae.
 18. The compound of claim 3, wherein R⁶ is —C(O)OH.19. The compound of claim 18, wherein R² is hydrogen, halogen, or C₁₋₆alkyl and R³ is hydrogen.
 20. The compound of claim 19, wherein each R¹²is independently hydrogen, halogen or C₁₋₆ alkoxy.